Mitochondrial Approaches for Neuroprotection

In the paper

“We observed significantly reduced cellular respiration and COX activity in myoblasts from HD patients, and these defects were exacerbated in chronic energy deprivation conditions (Chaturvedi et. al., unpublished findings).”

In the paper

“We found that oral administration of creatine at a dose of 8 g/day for 16 weeks is well tolerated, safe and bioavailable to the brain, and it decreased serum 8-hydroxy-2-deoxyguanosine levels, a marker for oxidative stress.”

What the sources say

• Not checked yetcites [134] Hersch SM 2006 Creatine in Huntington disease is safe, tolerable, bioavailable in brain and reduces serum 8OH2'dG Neurology 66 250 2 16434666 source

In the paper

“Recently, we found that CoQ10 treatment decreases brain oxidative stress, Aβ42 levels, β-amyloid plaque area and number, and improves cognitive performance in Tg19959 mice, a transgenic mouse model of AD (Kipiani et al., unpublished findings).”

What the sources say

• Not checked yetcites Kipiani et al., unpublished findings

In the paper

“We found that creatine significantly improves survival, improves motor performance, slows the development of brain atrophy, increases brain ATP levels, delays atrophy of striatal neurons and the formation of Htt-positive aggregates in the R6/2 and N-171-82Q transgenic mouse models of HD118-120.”

What the sources say

• Not checked yetcites [118] Andreassen OA 2001 Creatine increase survival and delays motor symptoms in a transgenic animal model of Huntington's disease Neurobiol Dis 8 479 91 11447996 source
• Not checked yetcites [119] Dedeoglu A 2003 Creatine therapy provides neuroprotection after onset of clinical symptoms in Huntington's disease transgenic mice J Neurochem 85 1359 67 12787055 PMC2866522 source
• Not checked yetcites [120] Ferrante RJ 2000 Neuroprotective effects of creatine in a transgenic mouse model of Huntington's disease J Neurosci 20 4389 97 10844007 PMC6772461 source

In the paper

“We found that creatine produced protection against dopamine loss, as well as an attenuation of neuron loss in the SN of mice treated with MPTP.”

In the paper

“In this study, oral administration of CoQ10 in PD patients was well tolerated and resulted in significant, dose-dependent increases in plasma CoQ10 levels.”

What the sources say

• Not checked yetcites [159] Shults CW 1997 Coenzyme Q10 levels correlate with the activities of complexes I and II/III in mitochondria from parkinsonian and nonparkinsonian subjects Ann Neurol 42 261 4 9266740 source

In the paper

“Both SS-31 and SS-20 also produce complete protection against MPTP neurotoxicity (Yang et al., unpublished findings).”

What the sources say

• Not checked yetcites Yang et al., unpublished findings

In the paper

“We found a significant reduction in CoQ10 levels in mitochondria isolated from platelets of PD patients, that directly correlated with a decrease in complex-I activity159.”

What the sources say

• Not checked yetcites [159] Shults CW 1997 Coenzyme Q10 levels correlate with the activities of complexes I and II/III in mitochondria from parkinsonian and nonparkinsonian subjects Ann Neurol 42 261 4 9266740 source

In the paper

“It reduces t-butylhydroperoxide induced ROS generation, attenuates MPTP-induced nigrostriatal dopaminergic neurodegeneration and reduces 3-NP induced striatal lesions.”

What the sources say

• Not checked yetcites Yang et al., unpublished findings

In the paper

“Mitochondrial dysfunction due to oxidative stress, mitochondrial DNA deletions, pathological mutations, altered mitochondrial morphology and interaction of pathogenic proteins with mitochondria leads to neuronal demise.”

In the paper

“Creatine was shown to reduce the UPDRS scores, and could not be rejected as futile based on the 30% DATATOP futility threshold.”

What the sources say

• Not checked yetcites [130] 2006 A randomized, double-blind, futility clinical trial of creatine and minocycline in early Parkinson disease Neurology 66 664 71 16481597 source

In the paper

“Oral administration of creatine produces a dose-dependent improvement in motor performance and extends survival in G93A transgenic ALS mice, where it protects against loss of both motor neurons and SN neurons114.”

What the sources say

• Not checked yetcites [114] Klivenyi P 1999 Neuroprotective effects of creatine in a transgenic animal model of amyotrophic lateral sclerosis Nat Med 5 347 50 10086395 source

In the paper

“There is ample evidence showing involvement of mitochondrial dysfunction in the pathogenesis of neurodegenerative disorders, therefore, one would predict that agents that alleviate mitochondrial dysfunction could be beneficial and exert neuroprotective effects.”

In the paper

“Similarly, we and others, by using CoQ10 and remacemide (NMDA antagonist) combination therapy observed significantly improved motor performance and increased survival in the R6/2 and the N-171-82Q transgenic mouse models of HD151, 154.”

What the sources say

• Not checked yetcites [151] Ferrante RJ 2002 Therapeutic effects of coenzyme Q10 and remacemide in transgenic mouse models of Huntington's disease J Neurosci 22 1592 9 11880489 PMC6758854 source
• Not checked yetcites [154] Schilling G 2001 Coenzyme Q10 and remacemide hydrochloride ameliorate motor deficits in a Huntington's disease transgenic mouse model Neurosci Lett 315 149 53 11716985 source

In the paper

“The combination therapy of CoQ10 and minocycline in R6/2 transgenic mouse model of HD resulted in a significantly increased amelioration of behavioral and neuropathological deficits, extended survival, improved rotarod performance and attenuated striatal neuron atrophy, as compared to either minocycline or CoQ10 alone153.”

What the sources say

• Not checked yetcites [153] Stack EC 2006 Combination therapy using minocycline and coenzyme Q10 in R6/2 transgenic Huntington's disease mice Biochim Biophys Acta 1762 373 80 16364609 source

In the paper

“A dose ranging and efficacy study of highdose coenzyme Q10 formulations in the R6/2 HD transgenic mice demonstrated that high-dose CoQ10 significantly extends survival, improves motor performance, grip strength and reduces brain atrophy in R6/2 HD mice, in a dose-dependent manner152.”

What the sources say

• Not checked yetcites [152] Smith KM 2006 Dose ranging and efficacy study of high-dose coenzyme Q10 formulations in Huntington's disease mice Biochim Biophys Acta 1762 616 26 16647250 source

In the paper

“Subsequently, in two other clinical trials, idebenone was safe and tolerable up to 360 mg/day and slowed progression of cognitive deficits in patients with AD168, 169.”

What the sources say

• Not checked yetcites [168] Gutzmann H Hadler D 1998 Sustained efficacy and safety of idebenone in the treatment of Alzheimer's disease: update on a 2-year double-blind multicentre study J Neural Transm Suppl 54 301 10 9850939 source
• Not checked yetcites [169] Gutzmann H 2002 Safety and efficacy of idebenone versus tacrine in patients with Alzheimer's disease: results of a randomized, double-blind, parallel-group multicenter study Pharmacopsychiatry 35 12 8 11819153 source

In the paper

“Mitochondrial-targeted antioxidants including mitochondrial CoQ10 (MitoQ) and Szeto-Schiller peptide (SS-31) play an important role in modulating ROS induced mitochondrial permeability transition and cell death, and were found to be protective in several in vitro and in vivo models of ischemia, reperfusion injury and neurodegeneration173.”

What the sources say

• Not checked yetcites [173] Armstrong JS 2007 Mitochondria-Directed Therapeutics. Antioxid Redox Signal 18092938

In the paper

“These findings strongly support the notion that creatine, CoQ10 and idebenone are promising neuroprotective agents in debilitating neurodegenerative disorders.”

In the paper

“Similarly, a novel peptide antioxidant (SS-31) targeted to the inner mitochondrial membrane prevents apoptosis, necrosis, oxidative stress and inhibition of the mitochondrial electron transport chain176.”

What the sources say

• Not checked yetcites [176] Szeto HH 2007 Mitochondria-Targeted Cytoprotective Peptides for Ischemia-Reperfusion Injury Antioxid Redox Signal 17999629

In the paper

“SS-31 protects neuronal cells against tert-butyl-hydroperoxide (tBHP) induced mitochondrial depolarization and apoptotic cell death by reducing intracellular ROS, decreasing markers of apoptotic cell death and caspase activity177.”

What the sources say

• Not checked yetcites [177] Zhao K 2005 Mitochondria-targeted peptide prevents mitochondrial depolarization and apoptosis induced by tert-butyl hydroperoxide in neuronal cell lines Biochem Pharmacol 70 1796 806 16216225 source

In the paper

“This trial was powered to be able to determine a 40% attenuation of total functional capacity decline with 80% power.”

What the sources say

• Not checked yetcites [155] 2001 A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington's disease Neurology 57 397 404 11502903 source

In the paper

“MitoQ reduces ROS formation and preserves mitochondrial function after glutathione depletion, even in the cells lacking mitochondrial DNA175.”

What the sources say

• Not checked yetcites [175] Lu C 2007 Is Antioxidant Potential of the Mitochondrial Targeted Ubiquinone Derivative MitoQ Conserved in Cells Lacking mtDNA? Antioxid Redox Signal 17999633

In the paper

“MitoQ is a derivative of CoQ10 conjugated to triphenylalkylphosphonium ions, which promotes uptake into mitochondria, where it can combat ROS originating in mitochondria174.”

What the sources say

• Not checked yetcites [174] Tauskela JS 2007 MitoQ--a mitochondria-targeted antioxidant IDrugs 10 399 412 17642004

In the paper

“The ratio of reduced to oxidized CoQ10 is significantly reduced in the platelets and cerebrospinal fluid (CSF) of PD patients156, 157 and in plasma of ALS patients158.”

What the sources say

• Not checked yetcites [156] Gotz ME 2000 Altered redox state of platelet coenzyme Q10 in Parkinson's disease J Neural Transm 107 41 8 10809402 source
• Not checked yetcites [157] Isobe C 2007 Increase of oxidized/total coenzyme Q-10 ratio in cerebrospinal fluid in patients with Parkinson's disease J Clin Neurosci 14 340 3 16647853 source
• Not checked yetcites [158] Sohmiya M 2005 An increase of oxidized coenzyme Q-10 occurs in the plasma of sporadic ALS patients J Neurol Sci 228 49 53 15607210 source

In the paper

“CoQ10 was safe and well tolerated at dosages of up to 1200 mg/day and a statistically significant dose-dependent reduction in UPDRS score was evident in subjects assigned to CoQ10 compared to those assigned to placebo.”

What the sources say

• Not checked yetcites [160] Shults CW 2002 Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline Arch Neurol 59 1541 50 12374491 source

In the paper

“However, plasma CoQ10 levels reached a plateau at the 2400 mg/day dosage and did not increase further at the 3000 mg/day dosage in PD, HD or ALS patients161, 162.”

What the sources say

• Not checked yetcites [161] Shults CW 2004 Pilot trial of high dosages of coenzyme Q10 in patients with Parkinson's disease Exp Neurol 188 491 4 15246848 source
• Not checked yetcites [162] Ferrante KL 2005 Tolerance of high-dose (3,000 mg/day) coenzyme Q10 in ALS Neurology 65 1834 6 16344537 source

In the paper

“SS-31 also prevents Ca2+ induced cytochrome c release and inhibits 3-NP-induced activation of the MPT pore and mitochondrial depolarization in isolated mitochondria178.”

What the sources say

• Not checked yetcites [178] Zhao K 2004 Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death, and reperfusion injury J Biol Chem 279 34682 90 15178689 source

In the paper

“Following activation by TP, Nrf2 dissociates from Keap1, translocates to the nucleus, and binds to the ARE promoter sequences, leading to coordinated induction of a battery of cytoprotective genes including antioxidant and anti-inflammatory genes182.”

What the sources say

• Not checked yetcites [182] Lee JM 2005 Nrf2, a multi-organ protector? Faseb J 19 1061 6 15985529 source

In the paper

“These studies suggest a potential neuroprotective effect of triterpenoids in cell and animal models of neurodegenerative disorders, and these compounds hold great promise as therapeutic agents for these disorders.”

In the paper

“In the Nrf2 knockout (Nrf2−/−) mice, injection of the mitochondrial complex-II inhibitor 3-NP causes increased motor deficits and striatal lesions as compared to the Nrf2+/+ mice, and these toxic effects of 3-NP were protected by adenoviral mediated over expression of Nrf2185.”

What the sources say

• Not checked yetcites [185] Shih AY 2005 Induction of the Nrf2-driven antioxidant response confers neuroprotection during mitochondrial stress in vivo J Biol Chem 280 22925 36 15840590 source

In the paper

“Sirtuin activation improves mitochondrial function, extends lifespan, and promotes longevity in various species including yeast193.”

What the sources say

• Not checked yetcites [193] Dali-Youcef N 2007 Sirtuins: the ‘magnificent seven’, function, metabolism and longevity Ann Med 39 335 45 17701476 source

In the paper

“Synthetic TP compounds are potent inducers of the antioxidant response element (ARE)–Nrf2–Keap1 signaling pathway and are useful in a variety of the cancers including leukemia, multiple myeloma, osteosarcoma, breast and lung cancer181.”

What the sources say

• Not checked yetcites [181] Liby KT Yore MM Sporn MB 2007 Triterpenoids and rexinoids as multifunctional agents for the prevention and treatment of cancer Nat Rev Cancer 7 357 69 17446857 source

In the paper

“Synthetic triterpenoids (TP), analogues of oleanolic acid, are powerful inhibitors of oxidative stress and cellular inflammatory processes, and thus may be neuroprotective in neurodegeneration.”

What the sources say

• Not checked yetcites [181] Liby KT Yore MM Sporn MB 2007 Triterpenoids and rexinoids as multifunctional agents for the prevention and treatment of cancer Nat Rev Cancer 7 357 69 17446857 source

In the paper

“Additionally, the Nrf2 activator tertbutylhydroquinone, has attenuated 3-NP toxicity in Nrf2+/+ mice, but not in Nrf2−/− mice185.”

What the sources say

• Not checked yetcites [185] Shih AY 2005 Induction of the Nrf2-driven antioxidant response confers neuroprotection during mitochondrial stress in vivo J Biol Chem 280 22925 36 15840590 source

In the paper

“Neuronal cultures derived from the Nrf2 knockout mice show increased susceptibility to oxidative stress, as well as damage produced by mitochondrial electron transport chain complex inhibitors such as MPP+ and rotenone184.”

What the sources say

• Not checked yetcites [184] Lee JM 2003 NF-E2-related factor-2 mediates neuroprotection against mitochondrial complex I inhibitors and increased concentrations of intracellular calcium in primary cortical neurons J Biol Chem 278 37948 56 12842875 source

In the paper

“These studies provide compelling evidence for a role of PGC-1α in the pathogenesis of neurodegenerative diseases, and thus it is a promising therapeutic target for neurodegenerative disorders2, 72.”

What the sources say

• Not checked yetcites [2] Lin MT Beal MF 2006 Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases Nature 443 787 95 17051205 source
• Not checked yetcites [72] McGill JK Beal MF 2006 PGC-1alpha, a new therapeutic target in Huntington's disease? Cell 127 465 8 17081970 source

In the paper

“Several agents, including creatine, CoQ10, MitoQ and idebenone are presently in clinical trials and show promising neuroprotective effects in these disorders.”

In the paper

“Identification of new therapeutic targets including PGC-1α and Sirtuins may provide new avenues for therapy of neurodegenerative diseases.”

In the paper

“SIRT-1 activation by resveratrol increases survival of motor neurons from transgenic ALS mice and reduces learning impairment and neurodegeneration in AD mouse models by decreasing the acetylation of SIRT1 substrates PGC-1α and p53194.”

What the sources say

• Not checked yetcites [194] Kim D 2007 SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis Embo J 26 3169 79 17581637 PMC1914106 source

In the paper

“Altogether, theses studies provide strong evidence for involvement of Sirtuins in neuroprotection and targeting of Sirtuins could be an attractive therapeutic approach in neurodegenerative disorders.”

In the paper

“Increased intracellular NAD+ concentration activates SIRT1 in brain following caloric restriction and this results in a reduction in amyloid pathology in a mouse model of Alzheimer disease197.”

What the sources say

• Not checked yetcites [197] Qin W 2006 Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer disease amyloid neuropathology by calorie restriction J Biol Chem 281 21745 54 16751189 source

In the paper

“Similarly, resveratrol in another study improved motor function in mice which was accompanied by a decrease in PGC1α acetylation leading to increased activity and mitochondrial biogenesis196.”

What the sources say

• Not checked yetcites [196] Lagouge M 2006 Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha Cell 127 1109 22 17112576 source

In the paper

“Therefore, therapeutic agents having the ability to target mitochondria and reduce mitochondrial dysfunction hold great promise for therapeutic interventions.”