CoChat
Sign Up
Cited by 504Parkinson's Disease Mechanisms and TreatmentsNerve injury and regenerationNuclear Receptors and Signaling

BDNF as a Promising Therapeutic Agent in Parkinson’s Disease

Open access
Palasz, Ewelina, Wysocka, Adrianna, Gasiorowska, Anna, Chalimoniuk, Malgorzata, Niewiadomski, Wiktor, Niewiadomska, Grazyna·2020·International Journal of Molecular Sciences
DOI 10.3390/ijms21031170PMC PMC7037114
Open this paper in CoChat — free accountOpen PDF

Abstract

Brain-derived neurotrophic factor (BDNF) promotes neuroprotection and neuroregeneration. In animal models of Parkinson’s disease (PD), BDNF enhances the survival of dopaminergic neurons, improves dopaminergic neurotransmission and motor performance. Pharmacological therapies of PD are symptom-targeting, and their effectiveness decreases with the progression of the disease; therefore, new therapeutical approaches are needed. Since, in both PD patients and animal PD models, decreased level of BDNF was found in the nigrostriatal pathway, it has been hypothesized that BDNF may serve as a therapeutic agent. Direct delivery of exogenous BDNF into the patient’s brain did not relieve the symptoms of disease, nor did attempts to enhance BDNF expression with gene therapy. Physical training was neuroprotective in animal models of PD. This effect is mediated, at least partly, by BDNF. Animal studies revealed that physical activity increases BDNF and tropomyosin receptor kinase B (TrkB) expression, leading to inhibition of neurodegeneration through induction of transcription factors and expression of genes related to neuronal proliferation, survival, and inflammatory response. This review focuses on the evidence that increasing BDNF level due to gene modulation or physical exercise has a neuroprotective effect and could be considered as adjunctive therapy in PD.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that BDNF has neuroprotective and neurorestorative effects on dopaminergic neurons and is a promising therapeutic target in Parkinson’s disease (PD), but direct exogenous BDNF delivery and BDNF gene therapy attempts have not succeeded clinically. It highlights physical exercise as a way to raise endogenous BDNF/TrkB signaling, with animal evidence for neuroprotection and human evidence for transient BDNF increases.

Key findings

  • In animal PD models, BDNF given before parkinsonism induction generally produced at least partial prevention of neuronal cell loss, increased survival of dopaminergic neurons in substantia nigra (SN), protected dopaminergic projections to striatum (ST), and increased dopamine in SN/ST; after 6-OHDA lesion, there was generally no recovery of dopaminergic neuron number in SN, although dopaminergic axon regrowth occurred when the Bdnf gene was transduced 6 weeks after axonal lesion.
  • Human BDNF therapy has been unsuccessful: subcutaneous recombinant methionyl human BDNF did not significantly affect ALS patient survival, and an intrathecal ALS trial in 25 patients (12-week, randomized, double-blinded, sequential, dose-escalation; 25, 60, 150, 400, or 1000 mg/day) found 150 mg/day well tolerated but was too small to conclude efficacy; no clinical research on BDNF gene therapy has been performed.
  • Exercise increased BDNF in animal PD models in midbrain, SN, ST, hippocampus, and cortex, and was accompanied by increased TH-ir neurons, TH protein, DA/DOPAC, DAT, and VMAT2; the TrkB inhibitor K252a abolished exercise-induced protection, and Bdnf+/− mice lacked exercise-induced dopaminergic neuroprotection.
  • In humans, acute aerobic exercise increases plasma/serum BDNF, but the effect is transient and returns to baseline within 10–60 min postexercise; a 40-min vigorous exercise at 80% heart rate reserve was most likely to produce significant BDNF elevation, and a meta-analysis of 100 ambulatory idiopathic PD patients (Hoehn/Yahr ≤3) found improvements in BDNF blood levels after physical activity in all six analyzed studies.

Methods

  • Design: narrative review; no primary experimental data are reported. It synthesizes evidence from animal PD models and human studies/trials on BDNF, direct delivery, gene therapy, and physical exercise.
  • Data/sample: cited animal models (e.g., 6-OHDA, MPTP) and human studies, including ALS trials (25 patients) and PD exercise studies/meta-analysis (100 patients); no primary sample is described.
  • Main analysis: narrative synthesis of cited literature; no formal systematic review or meta-analysis methods by the authors are stated. Mechanistic pathways discussed include TrkB, MAPK/ERK1/2, PI3K/Akt, CREB/TH, PGC1α/FNDC5, and GSK-3β.

Limitations

  • Stated in the paper: clinical trials with BDNF have met little success; no clinical research on BDNF gene therapy has been performed, so efficacy is unknown; delivery challenges include short half-life, poor bioavailability, limited blood-brain-barrier permeability, and off-target effects; the intrathecal ALS trial was too small to conclude efficacy; CSF BDNF results in PD are contradictory; the source of circulating BDNF after exercise is uncertain; and peripheral BDNF increases are transient.
  • Evident from the text: as a narrative review, it does not report a systematic search strategy, risk-of-bias assessment, or quantitative synthesis, and its conclusions rely heavily on animal models and indirect human evidence.
  • Evident from the text: many cited animal results are inconsistent or controversial (e.g., no increase in neuronal survival when BDNF was applied before 6-OHDA, no recovery of dopaminergic neuron number in SN after lesion, and decreased TrkB content in ST in one exercise study), which limits certainty.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3390/ijms21031170

Cites

204 of 204 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 230 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    Our study revealed a recovery of the intensity of VMAT2 immunostaining in substantia nigra in exercised MPTP mice.

    “Furthermore, our study revealed a recovery of the intensity of vesicular monoamine transporter 2 (VMAT2) immunostaining in SN in exercised MPTP mice, indicative of the increase in the number of dopaminergic neurons [125].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [125] Palasz, 2019, Exercise-Induced Neuroprotection and Recovery of Motor Function in Animal Models of Parkinson’s Disease, Front. Neurol. source

      Not checked in the free run.

  • Findingown data

    ELISA showed a significant increase in BDNF in both MPTP preceding training and follow-up training groups as compared to both controls and MPTP sedentary group in the midbrain including substantia nigra.

    “Similarly, enzyme-linked immunosorbent assay showed a significant increase in BDNF in both MPTP preceding training and follow-up training groups as compared to both controls and MPTP sedentary group in the midbrain including SN.”
    Quote in the paperSubstantial claim
  • Findingown data

    In striatum, training increased BDNF concentration in both MPTP groups of trained animals and the control trained group as compared to sedentary control and MPTP animals.

    “In ST, training increased BDNF concentration in both MPTP groups of trained animals and the control trained group as compared to sedentary control and MPTP animals.”
    Quote in the paperSubstantial claim
  • Findingown data

    In our study, higher BDNF and GDNF immunostaining intensity was noted in nigrostriatal areas of MPTP-treated mice which started treadmill training before and after intoxication, as compared to control groups both sedentary and exercised.

    “In our study, we also noted a higher BDNF and GDNF immunostaining intensity in nigrostriatal areas of MPTP-treated mice which started treadmill training before (preceding training) and after (follow-up training) intoxication, as compared to control groups both sedentary and exercised [125].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [125] Palasz, 2019, Exercise-Induced Neuroprotection and Recovery of Motor Function in Animal Models of Parkinson’s Disease, Front. Neurol. source

      Not checked in the free run.

  • Premisecitation

    In both PD patients and animal PD models, decreased level of BDNF was found in the nigrostriatal pathway.

    “Since, in both PD patients and animal PD models, decreased level of BDNF was found in the nigrostriatal pathway, it has been hypothesized that BDNF may serve as a therapeutic agent.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [59] Scalzo, 2010, Serum levels of brain-derived neurotrophic factor correlate with motor impairment in Parkinson’s disease, J. Neurol. source

      Not checked in the free run.

    • cites [60] Grah, 2014, Brain-derived neurotrophic factor as a suicide factor in mental disorders, Acta Neuropsychiatr. source

      Not checked in the free run.

    • cites [61] Ventriglia, 2013, Serum Brain-Derived Neurotrophic Factor Levels in Different Neurological Diseases, Biomed Res. Int. source

      Not checked in the free run.

    • cites [62] Howells, 2000, Reduced BDNF mRNA expression in the Parkinson’s disease substantia nigra, Exp. Neurol. source

      Not checked in the free run.

  • May combine two claims. 47
  • Classified as probably not a substantial claim. 6

  • May combine two claims.

    Premisecitation

    Decreased BDNF concentration in serum and brain is accompanied by an increase in degeneration of dopaminergic neurons in Parkinson's disease, leading to movement disorders, cognitive deficit, and mental disorders.

    “Decreased BDNF concentration in serum and brain is accompanied by an increase in degeneration of dopaminergic neurons in PD, which leads to movement disorders, cognitive deficit, and mental disorders [63,64,65,66]”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [63] Lin, J.-G., Chen, C.-J., Yang, H.-B., Chen, Y.-H., and Hung, S.-Y. (2017). Electroacupuncture Promotes Recovery of Motor Function and Reduces Dopaminergic Neuron Degeneration in Rodent Models of Parkinson’s disease. Int. J. Mol. Sci., 18. source

      Not checked in the free run.

    • cites [64] Wang, 2016, Low BDNF is associated with cognitive impairments in patients with Parkinson’s disease, Parkinsonism Relat. Disord. source

      Not checked in the free run.

    • cites [65] Huang, 2018, Serum concentration and clinical significance of brain-derived neurotrophic factor in patients with Parkinson’s disease or essential tremor, J. Int. Med. Res. source

      Not checked in the free run.

    • cites [66] Siuda, 2017, Cognitive impairment and BDNF serum levels, Neurol. Neurochir. Pol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BDNF promotes neuroprotection and neuroregeneration.

    “Brain-derived neurotrophic factor (BDNF) promotes neuroprotection and neuroregeneration.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [52] Awad, 2015, Potential role of growth factors in the management of spinal cord injury, World Neurosurg. source

      Not checked in the free run.

    • cites [53] Sampaio, 2017, Neurotrophic factors in Alzheimer’s and Parkinson’s diseases: Implications for pathogenesis and therapy, Neural Regen. Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    mBDNF exerts neuroprotective activity and promotes synaptic plasticity during adulthood.

    “A higher level of proBDNF is observed during brain development, while mBDNF exerts neuroprotective activity and promotes synaptic plasticity during adulthood [17,18,19,20,21].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [17] Yang, 2009, Neuronal release of proBDNF, Nat. Neurosci. source

      Not checked in the free run.

    • cites [18] Rauskolb, 2010, Global deprivation of brain-derived neurotrophic factor in the CNS reveals an area-specific requirement for dendritic growth, J. Neurosci. source

      Not checked in the free run.

    • cites [19] Yeh, 2012, Prenatal stress alters hippocampal synaptic plasticity in young rat offspring through preventing the proteolytic conversion of pro-brain-derived neurotrophic factor (BDNF) to mature BDNF, J. Physiol. source

      Not checked in the free run.

    • cites [20] Je, 2012, Role of pro-brain-derived neurotrophic factor (proBDNF) to mature BDNF conversion in activity-dependent competition at developing neuromuscular synapses, Proc. Natl. Acad. Sci. USA source

      Not checked in the free run.

    • cites [21] Antila, 2017, Neuronal plasticity and neurotrophic factors in drug responses, Mol. Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BDNF-TrkB signaling pathways regulate dendritic growth, synapse development, learning- and memory-processes-dependent synaptic plasticity, apoptosis, and survival of neurons.

    “BDNF-TrkB signaling pathways regulate multiple events, such as dendritic growth, pine maturation and stabilization [41,42,43], development of synapses [44,45], learning- and memory-processes-dependent synaptic plasticity [40,46,47], apoptosis, and survival of neurons [48,49,50,51].”
    Quote in the paperSubstantial claim0 of 8 sources checked
    • cites [41] Gorski, 2003, Brain-derived neurotrophic factor is required for the maintenance of cortical dendrites, J. Neurosci. source

      Not checked in the free run.

    • cites [42] Kwon, 2011, BDNF-Promoted Increases in Proximal Dendrites Occur via CREB-Dependent Transcriptional Regulation of Cypin, J. Neurosci. source

      Not checked in the free run.

    • cites [43] Orefice, 2013, Distinct Roles for Somatically and Dendritically Synthesized Brain-Derived Neurotrophic Factor in Morphogenesis of Dendritic Spines, J. Neurosci. source

      Not checked in the free run.

    • cites [44] Yoshii, 2014, Postsynaptic localization of PSD-95 is regulated by all three pathways downstream of TrkB signaling, Front. Synaptic Neurosci. source

      Not checked in the free run.

    • cites [45] Chen, 2017, Brain-Derived Neurotrophic Factor Increases Synaptic Protein Levels via the MAPK/Erk Signaling Pathway and Nrf2/Trx Axis Following the Transplantation of Neural Stem Cells in a Rat Model of Traumatic Brain Injury, Neurochem. Res. source

      Not checked in the free run.

    • cites [40] Leal, 2017, BDNF and Hippocampal Synaptic Plasticity, Vitam. Horm. source

      Not checked in the free run.

    • cites [46] Opazo, 2003, Phosphatidylinositol 3-Kinase Regulates the Induction of Long-Term Potentiation through Extracellular Signal-Related Kinase-Independent Mechanisms, J. Neurosci. source

      Not checked in the free run.

    • cites [47] Kay, 2013, Endogenous PI3K/Akt and NMDAR act independently in the regulation of CREB activity in lumbosacral spinal cord in cystitis, Exp. Neurol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Val66Met may increase susceptibility to Parkinson's disease in Europeans, but not in Asians.

    “An ethnicity-specific meta-analysis showed that Val66Met may increase susceptibility to PD in Europeans, but not in Asians, and increase the risk of suicidal behaviors in Asian and Caucasian populations [33].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Tsai, 2018, Critical Issues in BDNF Val66Met Genetic Studies of Neuropsychiatric Disorders, Front. Mol. Neurosci. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Neurotrophins prevent cell death and support neuronal proliferation and maturation, enhancing the growth and function of affected neurons in Alzheimer's disease and Parkinson's disease.

    “Neurotrophins prevent cell death and support neuronal proliferation and maturation, enhancing the growth and function of affected neurons in AD and PD [52,53].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [52] Awad, 2015, Potential role of growth factors in the management of spinal cord injury, World Neurosurg. source

      Not checked in the free run.

    • cites [53] Sampaio, 2017, Neurotrophic factors in Alzheimer’s and Parkinson’s diseases: Implications for pathogenesis and therapy, Neural Regen. Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Even though studies in animal models are promising, the effectiveness of neurotrophic factors in clinical studies remains unclear.

    “Even though studies in animal models are promising, their effectiveness in clinical studies remains unclear [53,54].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [53] Sampaio, 2017, Neurotrophic factors in Alzheimer’s and Parkinson’s diseases: Implications for pathogenesis and therapy, Neural Regen. Res. source

      Not checked in the free run.

    • cites [54] Pramanik, 2017, Neurotrophin Signaling and Stem Cells-Implications for Neurodegenerative Diseases and Stem Cell Therapy, Mol. Neurobiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Subcutaneous administration of recombinant methionyl human BDNF did not demonstrate a statistically significant effect on the survival of ALS patients and did not replicate the beneficial effect of BDNF obtained in phase I and II of the study.

    “A study with subcutaneous administration of recombinant methionyl human BDNF (r-metHuBDNF) did not demonstrate a statistically significant effect of BDNF on the survival of these patients and did not replicate the beneficial effect of BDNF obtained in I and II phase of the study [105].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [105] Bradley, 1999, A controlled trial of recombinant methionyl human BDNF in ALS, Neurology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Silencing the gene encoding BDNF in mice resulted in the loss of dopaminergic neurons, confirming the role of BDNF in protecting neurons against injury and degeneration.

    “Silencing the gene encoding BDNF in mice resulted in the loss of dopaminergic neurons, which confirms the role of BDNF in protecting neurons against injury and degeneration [72,75,76].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [72] Baquet, 2005, Brain-Derived Neurotrophic Factor Is Required for the Establishment of the Proper Number of Dopaminergic Neurons in the Substantia Nigra Pars Compacta, J. Neurosci. source

      Not checked in the free run.

    • cites [75] Gerecke, 2010, Exercise protects against MPTP-induced neurotoxicity in mice, Brain Res. source

      Not checked in the free run.

    • cites [76] Baker, 2005, Maturation but not survival of dopaminergic nigrostriatal neurons is affected in developing and aging BDNF-deficient mice, Brain Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A decrease in BDNF levels in Parkinson's disease may contribute to overexpression of alpha-synuclein and inhibition of dopamine synthesis.

    “There are data indicating that a decrease in BDNF levels in PD may contribute to overexpression of alpha-synuclein (ASN) and inhibition of dopamine (DA) synthesis [69,70,71].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [69] Kang, 2017, TrkB neurotrophic activities are blocked by α-synuclein, triggering dopaminergic cell death in Parkinson’s disease, Proc. Natl. Acad. Sci. USA source

      Not checked in the free run.

    • cites [70] Fang, 2017, Synuclein impairs trafficking and signaling of BDNF in a mouse model of Parkinson’s disease, Sci. Rep. source

      Not checked in the free run.

    • cites [71] Katila, 2017, Metformin lowers α-synuclein phosphorylation and upregulates neurotrophic factor in the MPTP mouse model of Parkinson’s disease, Neuropharmacology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Combined treatment with a D3 receptor agonist and BDNF in 6-OHDA lesioned rats led to stabilization of gait parameters, accelerated recovery of motor coordination and balance, and full recovery from muscle rigidity.

    “Combined treatment with a D3 receptor agonist and BDNF in 6-OHDA lesioned rats led to the stabilization of gait parameters, accelerated recovery of motor coordination and balance, and full recovery from muscle rigidity [96].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [96] Razgado-Hernandez, L.F., Espadas-Alvarez, A.J., Reyna-Velazquez, P., Sierra-Sanchez, A., Anaya-Martinez, V., Jimenez-Estrada, I., Bannon, M.J., Martinez-Fong, D., and Aceves-Ruiz, J. (2015). The transfection of BDNF to dopamine neurons potentiates the effect of dopamine D3 receptor agonist recovering the striatal innervation, dendritic spines and motor behavior in an aged rat model of Parkinson’s disease. PLoS ONE, 10. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BDNF participates in the regulation of tyrosine hydroxylase, which is also reduced in Parkinson's disease, consequently leading to motor disorders.

    “BDNF participates in the regulation of tyrosine hydroxylase (TH), which is also reduced in PD, consequently leading to motor disorders [72,73].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [72] Baquet, 2005, Brain-Derived Neurotrophic Factor Is Required for the Establishment of the Proper Number of Dopaminergic Neurons in the Substantia Nigra Pars Compacta, J. Neurosci. source

      Not checked in the free run.

    • cites [73] Baydyuk, 2011, Chronic deprivation of TrkB signaling leads to selective late-onset nigrostriatal dopaminergic degeneration, Exp. Neurol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BDNF administration increased dopamine level in substantia nigra and striatum and restored dopamine uptake in striatum.

    “Moreover, BDNF administration increased DA level in SN [92,100] and ST [88,92] and restored DA uptake in ST [101].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [92] Kim, 2012, AAV transduction of dopamine neurons with constitutively active rheb protects from neurodegeneration and mediates axon regrowth, Mol. Ther. source

      Not checked in the free run.

    • cites [100] Galpern, 1996, Cell-mediated delivery of brain-derived neurotrophic factor enhances dopamine levels in an MPP+ rat model of substantia nigra degeneration, Cell Transplant. source

      Not checked in the free run.

    • cites [88] Hung, 1996, The mesolimbic dopaminergic pathway is more resistant than the nigrostriatal dopaminergic pathway to MPTP and MPP+ toxicity: Role of BDNF gene expression, Mol. Brain Res. source

      Not checked in the free run.

    • cites [101] Levivier, 1995, Intrastriatal implantation of fibroblasts genetically engineered to produce brain-derived neurotrophic factor prevents degeneration of dopaminergic neurons in a rat model of Parkinson’s disease, J. Neurosci. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Alpha-synuclein overexpression downregulated BDNF transcription and impaired BDNF trafficking in neurons.

    “Moreover, it was reported that ASN overexpression downregulated BDNF transcription and impaired BDNF trafficking in neurons [53].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] Sampaio, 2017, Neurotrophic factors in Alzheimer’s and Parkinson’s diseases: Implications for pathogenesis and therapy, Neural Regen. Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Combined administration of an agonist of the D3 subtype of the dopamine receptor and gene-delivered BDNF markedly rescues dopaminergic neurons in substantia nigra and dopaminergic projections to striatum, and fully recovered the number of dopaminergic spines.

    “In contrast, Razgado-Hernandez et al. [96] noticed that the combined administration of agonist of D3 subtype of the dopamine receptor and gene-delivered BDNF are able to markedly rescue dopaminergic neurons in SN and dopaminergic projections to ST. Additionally, the treatment fully recovered the number of dopaminergic spines [96].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [96] Razgado-Hernandez, L.F., Espadas-Alvarez, A.J., Reyna-Velazquez, P., Sierra-Sanchez, A., Anaya-Martinez, V., Jimenez-Estrada, I., Bannon, M.J., Martinez-Fong, D., and Aceves-Ruiz, J. (2015). The transfection of BDNF to dopamine neurons potentiates the effect of dopamine D3 receptor agonist recovering the striatal innervation, dendritic spines and motor behavior in an aged rat model of Parkinson’s disease. PLoS ONE, 10. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BDNF increased survival of Nissl- or neuronal-nuclei-stained neuronal cells and dopaminergic neurons in substantia nigra and protected dopaminergic projections to striatum.

    “BDNF increased survival of Nissl- or neuronal-nuclei-stained neuronal cells [92,99,101] and dopaminergic neurons [89,92,93,99] in substantia nigra (SN) and protected dopaminergic projections to ST [92,93].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [92] Kim, 2012, AAV transduction of dopamine neurons with constitutively active rheb protects from neurodegeneration and mediates axon regrowth, Mol. Ther. source

      Not checked in the free run.

    • cites [99] Frim, 1994, Implanted fibroblasts genetically engineered to produce brain-derived neurotrophic factor prevent 1-methyl-4-phenylpyridinium toxicity to dopaminergic neurons in the rat, Proc. Natl. Acad. Sci. USA source

      Not checked in the free run.

    • cites [101] Levivier, 1995, Intrastriatal implantation of fibroblasts genetically engineered to produce brain-derived neurotrophic factor prevents degeneration of dopaminergic neurons in a rat model of Parkinson’s disease, J. Neurosci. source

      Not checked in the free run.

    • cites [89] Tsukahara, 1995, Effects of Brain-derived Neurotrophic Factor on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinsonism in Monkeys, Neurosurgery source

      Not checked in the free run.

    • cites [93] Nam, 2015, Induction of GDNF and BDNF by hRheb(S16H) Transduction of SNpc Neurons: Neuroprotective Mechanisms of hRheb(S16H) in a Model of Parkinson’s Disease, Mol. Neurobiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BDNF treatment with doses of 150 mg/day was well tolerated and provided BDNF concentration in cerebrospinal fluid that could be neuroprotective, but the number of patients included in the study was too small to make a conclusion about the efficacy of the treatment.

    “This clinical trial showed that BDNF treatment with doses of 150 mg/day was well tolerated and provided BDNF concentration in CSF that could be neuroprotective, but the number of patients included in the study was too small to make a conclusion about the efficacy of the treatment [106].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [106] Ochs, 2000, A phase I/II trial of recombinant methionyl human brain derived neurotrophic factor administered by intrathecal infusion to patients with amyotrophic lateral sclerosis, Amyotroph. Lateral Scler. Other Mot. Neuron Disord. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Even though BDNF does not induce neurogenesis, it exerts a positive influence on the remaining neurons.

    “Therefore, it seems that even though BDNF does not induce neurogenesis, it exerts a positive influence on the remaining neurons.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    In summary, BDNF treatment in animal models seemed to enhance dopaminergic neuron survival when administered before induction of Parkinson's disease or at least caused partial recovery of dopaminergic transmission despite lack of neurogenesis.

    “In summary, BDNF treatment in animal models seemed to enhance dopaminergic neurons survival when administered before induction of PD or at least caused partial recovery of dopaminergic transmission despite lack of neurogenesis (Figure 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In animal models of Parkinson's disease, exercise increased the number of TH-ir neurons in substantia nigra, the TH protein level in substantia nigra and striatum, and TH-ir fiber intensity in striatum.

    “In animal models of PD, exercise was able to increase the number of TH-ir neurons in SN [125,126,127,128,129,130,134], the TH protein level in SN [126,128] and ST [128,134], and TH-ir fiber intensity in ST [127,128].”
    Quote in the paperSubstantial claim0 of 7 sources checked
    • cites [125] Palasz, 2019, Exercise-Induced Neuroprotection and Recovery of Motor Function in Animal Models of Parkinson’s Disease, Front. Neurol. source

      Not checked in the free run.

    • cites [126] Lau, 2011, Neuroprotective effects and mechanisms of exercise in a chronic mouse model of Parkinson’s disease with moderate neurodegeneration, Eur. J. Neurosci. source

      Not checked in the free run.

    • cites [127] Tajiri, 2010, Exercise exerts neuroprotective effects on Parkinson’s disease model of rats, Brain Res. source

      Not checked in the free run.

    • cites [128] Real, 2013, BDNF receptor blockade hinders the beneficial effects of exercise in a rat model of Parkinson’s disease, Neuroscience source

      Not checked in the free run.

    • cites [129] Wu, 2011, Running exercise protects the substantia nigra dopaminergic neurons against inflammation-induced degeneration via the activation of BDNF signaling pathway, Brain Behav. Immun. source

      Not checked in the free run.

    • cites [130] Zhao, 2014, Protection of dopamine neurons by vibration training and up-regulation of brain-derived neurotrophic factor in a MPTP mouse model of Parkinson’s disease, Physiol. Res. source

      Not checked in the free run.

    • cites [134] Choe, 2012, Effects of Treadmill Exercise on the Recovery of Dopaminergic Neuron Loss and Muscle Atrophy in the 6-OHDA Lesioned Parkinson’s Disease Rat Model, Korean J. Physiol. Pharmacol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    To date, no clinical research on BDNF gene therapy has been performed.

    “To date, no clinical research on BDNF gene therapy has been performed.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    BDNF production is stimulated by both voluntary and forced physical activity.

    “BDNF production was shown to be stimulated by both voluntary [75] and forced physical activity [125,126,127,128,129,130,131,132,133].”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [75] Gerecke, 2010, Exercise protects against MPTP-induced neurotoxicity in mice, Brain Res. source

      Not checked in the free run.

    • cites [125] Palasz, 2019, Exercise-Induced Neuroprotection and Recovery of Motor Function in Animal Models of Parkinson’s Disease, Front. Neurol. source

      Not checked in the free run.

    • cites [126] Lau, 2011, Neuroprotective effects and mechanisms of exercise in a chronic mouse model of Parkinson’s disease with moderate neurodegeneration, Eur. J. Neurosci. source

      Not checked in the free run.

    • cites [127] Tajiri, 2010, Exercise exerts neuroprotective effects on Parkinson’s disease model of rats, Brain Res. source

      Not checked in the free run.

    • cites [128] Real, 2013, BDNF receptor blockade hinders the beneficial effects of exercise in a rat model of Parkinson’s disease, Neuroscience source

      Not checked in the free run.

    • cites [129] Wu, 2011, Running exercise protects the substantia nigra dopaminergic neurons against inflammation-induced degeneration via the activation of BDNF signaling pathway, Brain Behav. Immun. source

      Not checked in the free run.

    • cites [130] Zhao, 2014, Protection of dopamine neurons by vibration training and up-regulation of brain-derived neurotrophic factor in a MPTP mouse model of Parkinson’s disease, Physiol. Res. source

      Not checked in the free run.

    • cites [131] Tuon, 2014, Physical training prevents depressive symptoms and a decrease in brain-derived neurotrophic factor in Parkinson’s disease, Brain Res. Bull. source

      Not checked in the free run.

    • cites [132] Fredriksson, 2011, Running wheel activity restores MPTP-induced functional deficits, J. Neural Transm. source

      Not checked in the free run.

    • cites [133] Feitosa, 2017, The Treadmill Exercise Protects against Dopaminergic Neuron Loss and Brain Oxidative Stress in Parkinsonian Rats, Oxidative Med. Cell. Longev.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Some clinical trials report a direct, beneficial, but transient effect of GDNF on dopamine function, while others show no effect of GDNF treatment on Parkinson's disease progression and many side effects after its administration.

    “Some of them report the direct, beneficial, but transient effect of GDNF on DA function [107,108], and others show no effect of GDNF treatment on PD progression [109,110] and many side effects after its administration [110].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [107] Gill, 2003, Direct brain infusion of glial cell line–derived neurotrophic factor in Parkinson disease, Nat. Med. source

      Not checked in the free run.

    • cites [108] Slevin, 2007, Unilateral intraputamenal glial cell line–derived neurotrophic factor in patients with Parkinson disease: Response to 1 year of treatment and 1 year of withdrawal, J. Neurosurg. source

      Not checked in the free run.

    • cites [109] Kordower, 1999, Clinicopathological findings following intraventricular glial-derived neurotrophic factor treatment in a patient with Parkinson’s disease, Ann. Neurol. source

      Not checked in the free run.

    • cites [110] Whone, 2019, Randomized trial of intermittent intraputamenal glial cell line-derived neurotrophic factor in Parkinson’s disease, Brain source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Animal research on gene therapy demonstrates that viral vectors successfully transduced neurons and provided durable expression of BDNF.

    “Animal research on gene therapy additionally demonstrates that viral vectors successfully transduced neurons and provided the durable expression of BDNF [116,117,118,119].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [116] Bemelmans, 1999, Brain-Derived Neurotrophic Factor-Mediated Protection of Striatal Neurons in an Excitotoxic Rat Model of Huntington’s Disease, as Demonstrated by Adenoviral Gene Transfer, Hum. Gene Ther. source

      Not checked in the free run.

    • cites [117] Kells, 2004, AAV-Mediated gene delivery of BDNF or GDNF is neuroprotective in a model of huntington disease, Mol. Ther. source

      Not checked in the free run.

    • cites [118] Paradiso, 2009, Localized delivery of fibroblast growth factor–2 and brain-derived neurotrophic factor reduces spontaneous seizures in an epilepsy model, Proc. Natl. Acad. Sci. USA source

      Not checked in the free run.

    • cites [119] Nagahara, 2009, Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer’s disease, Nat. Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Physical activity led to normalization of dopamine content in substantia nigra and/or striatum and of DOPAC level in striatum, a slight increase in HVA content in striatum, and an elevation in DAT level in striatum.

    “Physical activity also led to a normalization of the DA content in SN and/or ST [75,126,129,130,132,133] and of 3,4-dihydroxyphenylacetic acid (DOPAC) level in ST [129,133], to a slight increase in the homovanillic acid (HVA) content in ST [133] and an elevation in the DAT level in ST [126,133].”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [75] Gerecke, 2010, Exercise protects against MPTP-induced neurotoxicity in mice, Brain Res. source

      Not checked in the free run.

    • cites [126] Lau, 2011, Neuroprotective effects and mechanisms of exercise in a chronic mouse model of Parkinson’s disease with moderate neurodegeneration, Eur. J. Neurosci. source

      Not checked in the free run.

    • cites [129] Wu, 2011, Running exercise protects the substantia nigra dopaminergic neurons against inflammation-induced degeneration via the activation of BDNF signaling pathway, Brain Behav. Immun. source

      Not checked in the free run.

    • cites [130] Zhao, 2014, Protection of dopamine neurons by vibration training and up-regulation of brain-derived neurotrophic factor in a MPTP mouse model of Parkinson’s disease, Physiol. Res. source

      Not checked in the free run.

    • cites [132] Fredriksson, 2011, Running wheel activity restores MPTP-induced functional deficits, J. Neural Transm. source

      Not checked in the free run.

    • cites [133] Feitosa, 2017, The Treadmill Exercise Protects against Dopaminergic Neuron Loss and Brain Oxidative Stress in Parkinsonian Rats, Oxidative Med. Cell. Longev.

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The BDNF-TrkB pathway upregulation by exercise shielded the dopaminergic neurons in substantia nigra from lipopolysaccharide-induced degeneration and 6-OHDA lesion in the animal model of Parkinson's disease.

    “It seemed that the BDNF-TrkB pathway upregulation by exercise shielded the dopaminergic neurons in SN from lipopolysaccharide-induced degeneration [129] and 6-OHDA lesion in the animal model of PD [128].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [129] Wu, 2011, Running exercise protects the substantia nigra dopaminergic neurons against inflammation-induced degeneration via the activation of BDNF signaling pathway, Brain Behav. Immun. source

      Not checked in the free run.

    • cites [128] Real, 2013, BDNF receptor blockade hinders the beneficial effects of exercise in a rat model of Parkinson’s disease, Neuroscience source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Long-term resistance and HIIT training reduced muscle tone and stiffness and had a positive effect on body balance in people with Parkinson's disease, osteoarthritis, and Alzheimer's disease.

    “Long-term resistance and HIIT training reduced muscle tone and stiffness and had a positive effect on body balance in people with PD, osteoarthritis, and AD [153,154,155,156].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [153] Marusiak, 2015, Interval training-induced alleviation of rigidity and hypertonia in patients with Parkinson’s disease is accompanied by increased basal serum brain-derived neurotrophic factor: A repeated-measures, case series pilot study, J. Rehabil. Med. source

      Not checked in the free run.

    • cites [154] Barriopedro, 2008, Exercise Training is Beneficial for Alzheimer’s Patients, Int. J. Sports Med. source

      Not checked in the free run.

    • cites [155] Brienesse, 2013, Effects of Resistance Training for People with Parkinson’s disease: A Systematic Review, J. Am. Med. Dir. Assoc. source

      Not checked in the free run.

    • cites [156] Bressel, 2014, High-Intensity Interval Training on an Aquatic Treadmill in Adults with Osteoarthritis, J. Strength Cond. Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These forms of activity led to a reduction of movement disorders and a decrease in cognitive deficit in patients with Parkinson's disease.

    “In addition, these forms of activity led to a reduction of movement disorders and a decrease in cognitive deficit in patients with PD [157].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [157] Skriver, 2014, Acute exercise improves motor memory: Exploring potential biomarkers, Neurobiol. Learn. Mem. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In animal models of Parkinson's disease, training is able to improve motor performance, namely movement and balance on a balance beam and motor memory in the rotarod test.

    “In addition, it was shown that, in animal models of PD, training is able to improve motor performance, namely movement and balance on a balance beam [126] and motor memory in rotarod test [129,133].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [126] Lau, 2011, Neuroprotective effects and mechanisms of exercise in a chronic mouse model of Parkinson’s disease with moderate neurodegeneration, Eur. J. Neurosci. source

      Not checked in the free run.

    • cites [129] Wu, 2011, Running exercise protects the substantia nigra dopaminergic neurons against inflammation-induced degeneration via the activation of BDNF signaling pathway, Brain Behav. Immun. source

      Not checked in the free run.

    • cites [133] Feitosa, 2017, The Treadmill Exercise Protects against Dopaminergic Neuron Loss and Brain Oxidative Stress in Parkinsonian Rats, Oxidative Med. Cell. Longev.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Acute aerobic, but not strength, exercise increased basal peripheral BDNF concentrations in healthy subjects, although the effect was transient.

    “A systematic and critical literature search conducted by Knaepen et al. [160] demonstrated that acute aerobic, but not strength, exercise increased basal peripheral BDNF concentrations in healthy subjects, although the effect was transient.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [160] Knaepen, 2010, Neuroplasticity—Exercise-Induced Response of Peripheral Brain-Derived Neurotrophic Factor, Sports Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A significant increase in serum BDNF in adult human males after aerobic exercise was indicated, whereof a 40 min-long vigorous exercise (80% heart rate reserve) was most likely to produce a significant BDNF elevation.

    “Also, a study performed by Schmolesky et al. [164] has indicated a significant increase in serum BDNF in adult human males after aerobic exercise, whereof a 40 min-long vigorous exercise (80% heart rate reserve) was most likely to produce a significant BDNF elevation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [164] Schmolesky, 2013, The effects of aerobic exercise intensity and duration on levels of brain-derived neurotrophic factor in healthy men, J. Sports Sci. Med.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Physical exercise increased spontaneous locomotor activity and subthreshold L-DOPA-induced activity and decreased depressive-like behavior in animal models of Parkinson's disease.

    “Moreover, physical exercise increased spontaneous locomotor activity and subthreshold L-DOPA-induced activity [133] and decreased depressive-like behavior, measured as immobility, in open field test [131].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [133] Feitosa, 2017, The Treadmill Exercise Protects against Dopaminergic Neuron Loss and Brain Oxidative Stress in Parkinsonian Rats, Oxidative Med. Cell. Longev.

      Not checked in the free run.

    • cites [131] Tuon, 2014, Physical training prevents depressive symptoms and a decrease in brain-derived neurotrophic factor in Parkinson’s disease, Brain Res. Bull. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Physical training decreased contralateral bias in the cylinder test and ipsilateral rotations in the amphetamine-induced rotational test and reduced rotational asymmetry in the apomorphine-induced rotational test.

    “Furthermore, physical training decreased contralateral bias in cylinder test [127] and ipsilateral rotations in amphetamine-induced rotational test [127,134] and reduced rotational asymmetry in apomorphine-induced rotational test [128,131,133].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [127] Tajiri, 2010, Exercise exerts neuroprotective effects on Parkinson’s disease model of rats, Brain Res. source

      Not checked in the free run.

    • cites [134] Choe, 2012, Effects of Treadmill Exercise on the Recovery of Dopaminergic Neuron Loss and Muscle Atrophy in the 6-OHDA Lesioned Parkinson’s Disease Rat Model, Korean J. Physiol. Pharmacol. source

      Not checked in the free run.

    • cites [128] Real, 2013, BDNF receptor blockade hinders the beneficial effects of exercise in a rat model of Parkinson’s disease, Neuroscience source

      Not checked in the free run.

    • cites [131] Tuon, 2014, Physical training prevents depressive symptoms and a decrease in brain-derived neurotrophic factor in Parkinson’s disease, Brain Res. Bull. source

      Not checked in the free run.

    • cites [133] Feitosa, 2017, The Treadmill Exercise Protects against Dopaminergic Neuron Loss and Brain Oxidative Stress in Parkinsonian Rats, Oxidative Med. Cell. Longev.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    An injection of K252a, an inhibitor of the BDNF receptor, was able to obliterate the protective effect of exercise on dopaminergic neuron number in substantia nigra and prevent the rise of TH protein level in substantia nigra and striatum.

    “An injection of K252a, an inhibitor of the BDNF receptor, was able to obliterate the protective effect of exercise on dopaminergic neuron number in SN [128,129] and prevent the rise of TH protein level in SN and ST [128].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [128] Real, 2013, BDNF receptor blockade hinders the beneficial effects of exercise in a rat model of Parkinson’s disease, Neuroscience source

      Not checked in the free run.

    • cites [129] Wu, 2011, Running exercise protects the substantia nigra dopaminergic neurons against inflammation-induced degeneration via the activation of BDNF signaling pathway, Brain Behav. Immun. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    The source of circulating BDNF in response to exercise is uncertain and widely discussed in the literature.

    “The source of circulating BDNF in response to exercise is uncertain and widely discussed in the literature.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    The release of BDNF from the brain during exercise may reflect an association between peripheral and central BDNF levels and highlight the plausibility of the hypothesis that the source of increased BDNF concentration due to exercise is the brain.

    “Although the permeability of BBB for BDNF is very limited, there is evidence for a release of BDNF from the brain during exercise [174,175], which may reflect an association between peripheral and central BDNF levels and highlight plausibility of the hypothesis according to which the source of increased BDNF concentration due to exercise would be”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [174] Rasmussen, 2009, Evidence for a release of brain-derived neurotrophic factor from the brain during exercise, Exp. Physiol. source

      Not checked in the free run.

    • cites [175] Klein, 2011, Blood BDNF concentrations reflect brain-tissue BDNF levels across species, Int. J. Neuropsychopharmacol. source

      Not checked in the free run.

    • The authors state this as an assumption: The brain is the main source of exercise-induced BDNF circulating in the blood.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Physical effort leads to a transient increase in BDNF synthesis in cells, from where excess BDNF can be released into the bloodstream, resulting in increased peripheral BDNF levels.

    “They suggested that physical effort leads to a transient increase in BDNF synthesis in cells, from where its excess can be released into the bloodstream, resulting in an increase in peripheral BDNF levels.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [160] Knaepen, 2010, Neuroplasticity—Exercise-Induced Response of Peripheral Brain-Derived Neurotrophic Factor, Sports Med. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    BDNF can be absorbed by central and/or peripheral nerve tissues, where it can induce neurotrophic and neuroprotective processes.

    “Then, BDNF can be absorbed by central and/or peripheral nerve tissues, in which it can induce neurotrophic and neuroprotective processes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Although the permeability of the blood-brain barrier for BDNF is very limited, there is evidence for a release of BDNF from the brain during exercise.

    “Although the permeability of BBB for BDNF is very limited, there is evidence for a release of BDNF from the brain during exercise [174,175], which may reflect an association between peripheral and central BDNF levels and highlight plausibility of the hypothesis according to which the source of increased BDNF concentration due to exercise would be”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [174] Rasmussen, 2009, Evidence for a release of brain-derived neurotrophic factor from the brain during exercise, Exp. Physiol. source

      Not checked in the free run.

    • cites [175] Klein, 2011, Blood BDNF concentrations reflect brain-tissue BDNF levels across species, Int. J. Neuropsychopharmacol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CREB binds to the TH gene promoter and increases TH transcription.

    “CREB binds to the appropriate sequence in the TH gene promoter, thereby increasing TH transcription [191,192].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [191] Guo, 1998, Regulation of tyrosine hydroxylase gene expression during transdifferentiation of striatal neurons: Changes in transcription factors binding the AP-1 site, J. Neurosci. source

      Not checked in the free run.

    • cites [192] Piech, 1997, Tyrosine Hydroxylase Gene Promoter Activity Is Regulated by Both Cyclic AMP-responsive Element and AP1 Sites following Calcium Influx, J. Biol. Chem. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The number of studies regarding the BDNF level in cerebrospinal fluid in Parkinson's disease is limited, and their results are contradictory.

    “The number of studies regarding the BDNF level in CSF in PD is limited, and their results are contradictory [165,166].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [165] Zhang, 2008, CSF Multianalyte Profile Distinguishes Alzheimer and Parkinson Diseases, Am. J. Clin. Pathol. source

      Not checked in the free run.

    • cites [166] Salehi, 2009, Brain-derived neurotrophic factor concentrations in the cerebrospinal fluid of patients with Parkinson’s disease, J. Clin. Neurosci. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BDNF binds to the TrkB receptor on the surface of the neurovascular unit and triggers intracellular signals transmitted primarily by MAPK/ERK1/2 and CaMKII, which are responsible for phosphorylation of CREB.

    “BDNF binds to the TrkB receptor on the surface of the neurovascular unit and triggers a cascade of intracellular signals, transmitted primarily by MAPK/ERK1/2 and calcium and calmodulin-dependent protein kinase II (CaMKII), which are responsible for phosphorylation of cAMP-response element-binding protein (CREB, transcription factor, key for long-term neuronal plasticity).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [191] Guo, 1998, Regulation of tyrosine hydroxylase gene expression during transdifferentiation of striatal neurons: Changes in transcription factors binding the AP-1 site, J. Neurosci. source

      Not checked in the free run.

    • cites [192] Piech, 1997, Tyrosine Hydroxylase Gene Promoter Activity Is Regulated by Both Cyclic AMP-responsive Element and AP1 Sites following Calcium Influx, J. Biol. Chem. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exercises increase transcription of PGC1α, which in complex with estrogen-related receptor alpha can stimulate expression of FNDC5 in the brain.

    “In addition, exercises increase transcription of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), a protein that regulates mitochondrial biogenesis, which, in complex with estrogen-related receptor alpha, can stimulate the expression of myokine, the fibronectin type III domain-containing protein 5 (FNDC5) in the brain [187].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [187] Wrann, 2013, Exercise Induces Hippocampal BDNF through a PGC-1α/FNDC5 Pathway, Cell Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Platelets store circulating BDNF secreted by the brain and can release it back into the bloodstream.

    “Platelets store circulating BDNF secreted by the brain, which they then can release back into the bloodstream [173].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [173] Walsh, 2018, Exercise and circulating BDNF: Mechanisms of release and implications for the design of exercise interventions, Appl. Physiol. Nutr. Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Matthews et al. and Pratesi et al. found an increase in BDNF mRNA expression in skeletal muscle in humans after physical effort and after electrical stimulation, but no release into the blood was observed.

    “In their studies, Matthews et al. [168] and Pratesi et al. [169] found an increase in BDNF mRNA expression in skeletal muscle in humans after physical effort and after electrical stimulation, but no release into the blood was observed.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [168] Matthews, 2009, Brain-derived neurotrophic factor is produced by skeletal muscle cells in response to contraction and enhances fat oxidation via activation of AMP-activated protein kinase, Diabetologia source

      Not checked in the free run.

    • cites [169] Pratesi, 2013, Skeletal muscle: An endocrine organ, Clin. Cases Miner. Bone Metab.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Although neurons in muscles produce BDNF as a result of exercise, it does not enter the bloodstream.

    “Although neurons in muscles produce BDNF as a result of exercise, it does not enter the bloodstream.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [168] Matthews, 2009, Brain-derived neurotrophic factor is produced by skeletal muscle cells in response to contraction and enhances fat oxidation via activation of AMP-activated protein kinase, Diabetologia source

      Not checked in the free run.

    • cites [169] Pratesi, 2013, Skeletal muscle: An endocrine organ, Clin. Cases Miner. Bone Metab.

      Not checked in the free run.

    • cites [170] Zhang, 2019, BDNF contributes to the skeletal muscle anti-atrophic effect of exercise training through AMPK-PGC1α signaling in heart failure mice, Arch. Med. Sci. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationreasoning

    Dopaminergic neurons protected by NTs do not degenerate and thus do not send signals mobilizing the proinflammatory response.

    “This is because dopaminergic neurons protected by NTs do not degenerate and thus do not send signals mobilizing the proinflammatory response.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    GSK-3 stimulates release of IL-1β, IL-6, and TNFα in activated microglia and inhibits release of anti-inflammatory cytokines like IL-10.

    “GSK-3 stimulates the release of interleukin 1 beta (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor alpha in activated microglia and inhibits the release of anti-inflammatory cytokines like interleukin 10 (IL-10) [205].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [205] Green, 2012, GSK-3 mediates the release of IL-1β, TNF-α and IL-10 from cortical glia, Neurochem. Int. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The presence of both IGF-1 and BDNF is required for the viability and proper functioning of neuronal cells.

    “Some authors indicate that the presence of both IGF-1 and BDNF is required for the viability and proper functioning of neuronal cells [186].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [186] Zheng, 2004, Comparative signaling pathways of insulin-like growth factor-1 and brain-derived neurotrophic factor in hippocampal neurons and the role of the PI3 kinase pathway in cell survival, J. Neurochem. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Physical exercise increases secretion of IGF-I and VEGF which, together with BDNF, can improve memory by modulating synaptic plasticity, synapses, and neurotransmission in mature neurons.

    “Physical exercise is known to increase the secretion of IGF-I and vascular endothelial growth factor (VEGF) which, together with BDNF, can improve memory by modulating synaptic plasticity, synapses, and neurotransmission in mature neurons [202].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [202] Maass, 2016, Relationships of peripheral IGF-1, VEGF and BDNF levels to exercise-related changes in memory, hippocampal perfusion and volumes in older adults, Neuroimage source

      Not checked in the free run.

50 of 50

  • The paper relies on this without support.

    Current pharmacological therapies for Parkinson’s disease are symptom-targeting and their effectiveness decreases with disease progression, motivating the need for new therapeutic approaches.

    “Pharmacological therapies of PD are symptom-targeting, and their effectiveness decreases with the progression of the disease; therefore, new therapeutical approaches are needed.”

  • The paper relies on this without support.

    Animal models of Parkinson’s disease adequately model human Parkinson’s disease for the neuroprotective effects of BDNF.

    “In animal models of Parkinson’s disease (PD), BDNF enhances the survival of dopaminergic neurons, improves dopaminergic neurotransmission and motor performance.”

  • The authors state this as an assumption.

    The brain is the main source of exercise-induced BDNF circulating in the blood.

    “An increase in BDNF serum levels after exercise may be explained by the assumption that the brain is the main source of exercise-induced BDNF circulating in the blood [171,172,173].”

  • The paper relies on this without support.

    A single exercise causes a short-lived BDNF increase in the blood of patients with PD and is not associated with improvement in neurological status.

    “Even though a single exercise causes a BDNF increase in the blood of patients with PD, it is short-lived and is not associated with an improvement in the neurological status of the patients.”

  • The paper relies on this without support.

    Neither direct delivery of exogenous BDNF into the patient’s brain nor attempts to enhance BDNF expression with gene therapy have been successful in PD.

    “However, neither direct delivery of exogenous BDNF into the patient’s brain nor attempts to enhance BDNF expression with gene therapy turned out successful.”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • BDNF gene therapy is called unsuccessful despite no clinical trials

    Minor

    The conclusion says attempts to enhance BDNF expression with gene therapy were unsuccessful, but the paper states that no clinical research on BDNF gene therapy has been performed. It therefore cannot report a failed clinical outcome for that approach.

1 of 1

Cites

1 retracted

Flagged first, then by citations

Research works printed but not linked: 3

  1. Awad, 2015, Potential role of growth factors in the management of spinal cord injury, World Neurosurg., 83, 120, 10.1016/j.wneu.2013.01.042 · DOI
  2. Filus, 2010, Serum BDNF levels and intensity of depressive symptoms, Neuropsychiatr. Neuropsychol., 5, 155
  3. Piotrowicz, 2017, Alterations in serum BDNF and catecholamines during exercise to volitional exhaustion—The influence of normobaric hypoxia and endurance training, Folia Neuropathol., 55, 173

Cited by

Sorted by citations

Authors
Palasz, E., Wysocka, A., Gasiorowska, A., Chalimoniuk, M., Niewiadomski, W., & Niewiadomska, G.
Affiliations
  • Mossakowski Medical Research Centre Polish Academy of Sciences, 02-106 Warsaw, Poland
  • Instytut Biologii Doświadczalnej im. Marcelego Nenckiego (PL)
  • Faculty in Biala Podlaska, Jozef Pilsudski University of Physical Education in Warsaw, 21-500 Warszawa, Poland
  • Mossakowski Medical Research Institute, Polish Academy of Sciences (PL)
  • Nencki Institute of Experimental Biology Polish Academy of Sciences, 02-093 Warsaw, Poland
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2020-02-10
Volume
21
Issue
3
Pages
1170
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms21031170
PMC
PMC7037114
OpenAlex
W3004443958
Cited by
504
References
204
Citations by year
2026: 48 · 2025: 104 · 2024: 84 · 2023: 100 · 2022: 89 · 2021: 62 · 2020: 17
FWCI
7.53
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
Keywords
brain-derived neurotrophic factor, Parkinson's disease, neuroprotection, dopaminergic neurons, nigrostriatal pathway, TrkB receptor, physical activity, gene therapy, neurodegeneration, adjunctive therapy, neuroinflammation
MeSH terms
Animals, Humans, Parkinson Disease, Neuroprotective Agents, Brain-Derived Neurotrophic Factor

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review