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PreprintCited by 26Traumatic Brain Injury and Neurovascular DisturbancesStress Responses and CortisolTraumatic Brain Injury Research

The Role of Apoptosis and Autophagy in the Hypothalamic-Pituitary-Adrenal (HPA) Axis After Traumatic Brain Injury (TBI)

Open access
Taheri, Serpil, Karaca, Zuleyha, Mehmetbeyoglu, Ecmel, Hamurcu, Zuhal, Yılmaz, Zeynep, Dal, Fatma, Cınar, Venhar, Ulutabanca, Halil +4 more·2022·International Journal of Molecular Sciences
DOI 10.21203/rs.3.rs-1159219/v1PMC PMC9778890
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Abstract

Traumatic brain injury (TBI) is one of the major health problems affecting millions of people worldwide leading to death or permanent damage. TBI affects the hypothalamic-pituitary-adrenal (HPA) axis either by primary injury to the hypothalamic-hypophyseal region or by secondary vascular damage, brain, and/or pituitary edema, vasospasm, and inflammation. Neuroendocrine dysfunctions after TBI have been clinically described in all hypothalamic-pituitary axes. In this study, we focused on the HPA axis-related tissues in the acute and chronic phases of TBI to determine the role of autophagy and apoptosis in the development of endocrine disturbances after TBI.We established a mild TBI (mTBI) in rats using the controlled cortical impact (CCI) model. The hypothalamus, pituitary, and adrenal tissues were collected in the acute (24 hours) and chronic (30 days) groups after TBI; and we investigated autophagy (Lc3, Bcln1, P150, Ulk, and Atg5 ) and apoptosis (pro-caspase-3, cleaved caspase-3) markers in the HPA axis-related tissues using RT-PCR and Western blotting assays.The present data showed that after mTBI, P150 and Atg5 transcripts showed a stable decrement from the acute to chronic phases in the hypothalamus, pituitary, and adrenal glands. In contrast, Bcln1 transcripts were found to be only affected in the adrenal glands, with a prominent increase during the chronic phase. We also evaluated the levels of TNF-α and corticosterone by western blot in the HPA axis-related tissues in the acute and chronic phases after TBI. The increased corticosterone levels in the adrenal glands pointed out the activation of the HPA axis, while high TNF-α levels in the hypothalamus, pituitary, and adrenal glands suggested neuroinflammation.As a result, transcripts related to autophagy were reduced in the hypothalamus, pituitary, and adrenals after TBI; but this was not reflected in autophagy-related protein levels. In contrast, protein markers related to apoptosis increased in the adrenal glands during the acute phase and in the pituitary during the chronic phase. TBI seems to trigger apoptosis by inducing inflammation that can also affect the adrenals in the acute phase; and this situation may lead to an impairment of communication through the hypothalamus, pituitary and adrenal glands. This may explain the permanent damage to the pituitary with increased apoptosis and inflammation in the chronic phase. These findings may contribute to the elucidation of the underlying mechanisms of endocrine dysfunctions such as pituitary and adrenal insufficiency that occur after TBI. Although adrenals are not directly affected by TBI, we suggest that the role of the adrenals together with the hypothalamus and pituitary should not be ignored in the acute phase after TBI.

AI snapshot

Written from the paper’s full text.

TL;DR

In a rat mild controlled cortical impact model, TBI altered autophagy-related transcripts and increased corticosterone/TNF-α in HPA tissues, but autophagy protein markers Lc3 and Beclin-1 did not change. Cleaved caspase-3 increased in the adrenal glands acutely and in the pituitary chronically, suggesting tissue-specific apoptotic and inflammatory responses after TBI.

Key findings

  • In the hypothalamus and pituitary, P150 and Atg5 transcripts were significantly decreased in the acute phase and further decreased in the chronic phase versus sham (hypothalamus P150: p=0.0004 acute, p<0.001 chronic; Atg5: p=0.0012 acute, p=0.001 chronic).
  • In the adrenals, Bcln1 was the only transcript increased in the chronic TBI group versus acute TBI and sham (p=0.007); Ulk, P150, and Atg5 were significantly decreased in the acute phase (p=0.011, p=0.031, p=0.023, respectively), with Ulk and Atg5 significant only acutely (Ulk p=0.025; Atg5 p=0.023).
  • Corticosterone levels increased in adrenal tissue in both acute and chronic phases, and TNF-α increased in the hypothalamus, pituitary, and adrenals in both phases; TNF-α was not detectable in the sham hypothalamus.
  • Despite transcript changes, Beclin-1 and Lc3 protein levels were similar across groups in all tissues; cleaved caspase-3 increased in the adrenal in the acute phase and in the pituitary in the chronic phase, but was not detectable in the hypothalamus.

Methods

  • A total of 42 healthy 8-week-old adult male Sprague-Dawley rats weighing 250–300 g were used; experiments were randomized and controlled double-blind. Groups were sham, acute TBI sacrificed at 24 hours, and chronic TBI sacrificed at 30 days. mRNA analyses were performed on 14 rats per group and Western blot analyses on 9 rats per group because enough protein was not obtained; the power analysis text states a total of 27 male rats were used, while the experimental design states each group included 14 rats.
  • Mild TBI was induced by controlled cortical impact (CCI): left parasagittal craniectomy 2 mm lateral to the sagittal suture and 2 mm posterior to bregma, with mild CCI at 20 psi and 1.5 mm.
  • RT-PCR measured Ulk, P150, Atg5, and Bcln1 transcripts with Actb as housekeeping gene and 2^-ΔΔCt normalization; Western blot measured Tnf-α, corticosterone, Lc3, Beclin-1, pro-caspase-3, cleaved caspase-3, and β-actin. Statistics used one-way ANOVA or Kruskal-Wallis for gene expression and unpaired t-test or Mann-Whitney U for protein expression, with p<0.05 considered significant.

Limitations

  • Stated: the authors note that more investigation is required on the adrenal response after TBI, and they suggest the lack of hypothalamic cleaved caspase-3 change may be associated with differences in the model systems used.
  • Evident: only male rats and a mild CCI model were studied, limiting generalization by sex and injury severity; sample-size reporting is inconsistent (42 rats described, power analysis says 27, groups described as 14 each, and Western blot n=9).
  • Evident: autophagy transcript changes did not translate into Lc3 or Beclin-1 protein changes, and the paper does not resolve this transcript–protein mismatch.

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

Integrity signals

Registry

Crossref · 10.21203/rs.3.rs-1159219/v1

Cites

38 of 38 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 35 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    TNF-α protein levels increased in the hypothalamus, pituitary and adrenals in the acute and chronic phase after mild CCI.

    “In addition, increased TNF-α protein levels in the hypothalamus, pituitary and adrenals in the acute and chronic phase after mild CCI were also evidence of increased neuroinflammation.”
    Quote in the paperSubstantial claim
  • Findingown data

    Corticosterone levels in the adrenals increase in the acute and chronic phases after mild CCI, as a sign of HPA axis activation.

    “We have shown that the corticosterone levels, as a sign of the HPA axis activation in the adrenals, in the acute and chronic phases after mild CCI model, increase as expected.”
    • Also stated in: § 4. Discussion · plain
      “The present study revealed the increased ratio of apoptosis in the acute phase of TBI in the adrenal glands, in contrast, corticosterone levels were increased both in the acute and chronic phases after TBI (Garrahy and Agha 2016;Taheri et al. 2021).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The HPA axis is responsible for providing an adequate cortisol response to maintain homeostasis in stressful situations, such as TBI.
  • Findingown data

    After mTBI, Atg5 transcripts showed a stable decrement from the acute to chronic phases in the hypothalamus, pituitary, and adrenal glands.

    “The present data showed that after mTBI, P150 and Atg5 transcripts showed a stable decrement from the acute to chronic phases in the hypothalamus, pituitary, and adrenal glands.”
    Quote in the paperSubstantial claim
  • Findingown data

    Protein markers related to apoptosis increased in the pituitary during the chronic phase after TBI.

    “In contrast, protein markers related to apoptosis increased in the adrenal glands during the acute phase and in the pituitary during the chronic phase.”
    Quote in the paperSubstantial claim
  • Findingown data

    Bcln1 transcript levels were slightly, albeit not significantly, lower in the hypothalamus and pituitary during the acute and chronic phases of TBI than the sham group.

    “Among the four transcripts tested, the Bcln1 transcript levels were slightly, albeit not significantly lower in the hypothalamus and pituitary during the acute (respectively, dF=2,2; p=0,41 and p>0,99) and chronic phases (respectively, dF=2,2; p=0,73 and p>0,15) of TBI than the sham group (Figures 3A and 3B).”
    Quote in the paperNot a substantial claim
  • May combine two claims. 17
  • Classified as probably not a substantial claim. 21
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingown data

    Ulk transcript levels were decreased in adrenal tissue compared to the sham group in the acute and chronic phases of TBI, with significant decrease only in the acute phase.

    “The levels of the Ulk and Atg5 transcripts were decreased compared to the sham group in the acute and chronic phases of TBI.The decrease was significant in the adrenal only in the acute phase (Ulk: dF=2, p=0.025;Atg5: dF=2, p=0.023) (Figure 3C).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Ulk transcripts were reduced in the pituitary during the acute phase of TBI, but this reduction was not maintained during the chronic phase.

    “but in the pituitary during the acute phase Ulk transcripts were reduced (dF=2; p=0,049), which was not maintained during the chronic phase (dF=2; p>0,99) (Figure 3B).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Atg5 transcript levels were decreased in adrenal tissue compared to the sham group in the acute and chronic phases of TBI, with significant decrease only in the acute phase.

    “The levels of the Ulk and Atg5 transcripts were decreased compared to the sham group in the acute and chronic phases of TBI.The decrease was significant in the adrenal only in the acute phase (Ulk: dF=2, p=0.025;Atg5: dF=2, p=0.023) (Figure 3C).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Bcln1 transcripts were only affected in the adrenal glands, with a prominent increase during the chronic phase after mTBI.

    “In contrast, Bcln1 transcripts were found to be only affected in the adrenal glands, with a prominent increase during the chronic phase.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    LC3-II expression is widely considered to be a sign of autophagy induction.

    “As a result, Lc3-II expression is widely considered to be a sign of autophagy induction (Lee et al. 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Lee et al. 2016

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Prolonged TNF-α production is harmful to neurons and leads to apoptosis and autophagy.

    “Prolonged TNF-α production is harmful to neurons and leads to apoptosis and autophagy (Wolf et al. 2019;Wu and Lipinski 2019).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Wolf et al. 2019

      Not checked in the free run.

    • cites Wu and Lipinski 2019

      Not checked in the free run.

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

    Study design and conductnone given

    All western blot experiments were independently repeated at least twice.

    “All western blot experiments were independently repeated at least twice.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The male rats were randomly divided into three groups, and each group included 14 rats.

    “The male rats were randomly divided into three groups, and each group included 14 rats.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    TNF-α activation can start a cascade of inflammatory reactions.

    “TNF-α is a downstream inflammatory signaling pathway initiator, and its activation can start a cascade of inflammatory reactions (Tapp et al. 2019).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Tapp et al. 2019

      Not checked in the free run.

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

    Study design and conductown data

    Sample size was calculated with power analysis: alpha 0.05, power 0.95, effect size 0.82, minimum 9 per group; a total of 27 male rats was used.

    “As a result of the power analysis, the amount of Type I error (alpha) was 0.05, the power of the test (1-beta) was 0.95, and the effect size was 0.82 while using the Independent Samples One-Way ANOVA test for minimum sample size required a significant difference of 9 for each group; a total of 27 male rat was used.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites G-power (v3.1)

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TBI affects the HPA axis either by direct injury to the hypothalamic-hypophyseal region or by secondary vascular damage, brain and/or pituitary edema, vasospasm, and inflammation.

    “TBI affects the HPA axis either by direct injury to the hypothalamic-hypophyseal region or by secondary vascular damage, brain and/or pituitary edema, vasospasm, and inflammation (Özben 1998;Hiebert et al. 2015;Mckee and Daneshvar 2015).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Özben 1998

      Not checked in the free run.

    • cites Hiebert et al. 2015

      Not checked in the free run.

    • cites Mckee and Daneshvar 2015

      Not checked in the free run.

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

    Study design and conductnone given

    All experiments were performed on randomized and controlled double-blind.

    “All experiments were performed on randomized and controlled double-blind.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Beclin-1 and Lc3 proteins are crucial autophagy mediators and are involved in distinct phases of the autophagic process.

    “Both Beclin-1 and Lc3 proteins are crucial autophagy mediators and are involved in distinct phases of the autophagic process (Ueno et al. 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ueno et al. 2016

      Not checked in the free run.

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

    Premisecitation

    Abnormalities that emerge after TBI are temporary in most patients but can be permanent in some.

    “Although these abnormalities that emerge after TBI are temporary in most patients, they can be permanent in some (Tanriverdi et al. 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Tanriverdi et al. 2015

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). The quote only partly states this claim.

    Study design and conductcitation

    All antibodies were validated and made ready for use by the supplier company according to the antibody validation principle of Uhlen et al.

    “All of the antibodies were validated and made ready for use by the supplier company”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Bordeaux et al. 2010

      Not checked in the free run.

    • cites Uhlen et al. 2016

      Not checked in the free run.

    • cites Hamurcu et al. 2018

      Not checked in the free run.

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

    Premisecitation

    TBI can result in HPA axis dysfunction characterized by decreased cortisol levels.

    “On the other hand, TBI can also result in the HPA axis dysfunction characterized by decreased cortisol levels (Taylor et al. 2008).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Taylor et al. 2008

      Not checked in the free run.

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

    Premisecitation

    Adrenal insufficiency due to suppressed activation of the HPA axis emerges in 11-13 percent of all TBI cases.

    “Adrenal insufficiency due to suppressed activation of the HPA axis emerges in 11-13 percent of all TBI cases, according to clinical evidence (Tanriverdi et al. 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Tanriverdi et al. 2015

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Transcripts related to autophagy were reduced in the hypothalamus, pituitary, and adrenals after TBI, but this was not reflected in autophagy-related protein levels.

    “As a result, transcripts related to autophagy were reduced in the hypothalamus, pituitary, and adrenals after TBI; but this was not reflected in autophagy-related protein levels.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    All PCR experiments for detecting transcript levels were repeated at least twice independently and blindly.

    “All PCR experiments for detecting transcript levels were repeated at least twice independently and blindly.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Corticosterone and TNF-α protein levels are measured from sera to detect activation and neuroinflammation in the HPA axis.

    “Generally, corticosterone and TNF-α protein levels are measured from the sera to detect the activation and neuroinflammation in the HPA axis (Taylor et al. 2008).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Taylor et al. 2008

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TBI leads to primary and secondary injury, the latter including edema, disturbed blood flow, and neuroinflammation, and has been implicated in post-injury neuroendocrine diseases such as neuropsychiatric disorders and pituitary insufficiency.

    “TBI leads to two types of injury, the primary and secondary injury which includes edema, disturbed blood flow, and neuroinflammation, and has been implicated in the development of post-injury neuroendocrine diseases such as neuropsychiatric disorders and pituitary insufficiency (Tanriverdi et al. 2010).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Tanriverdi et al. 2010

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TBI raises serum corticosterone levels in rats, which peak at 3 hours after TBI compared to controls and return to normal by 5 hours after TBI.

    “Following the injury, TBI raises serum corticosterone levels, which peak at 3 hours after TBI compared to controls and return to normal by 5 hours after TBI in rats.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Taylor et al. 2008

      Not checked in the free run.

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

    Study design and conductnone given

    All PCR experiments and western blot analyses for detecting transcript and protein levels were repeated at least twice independently and blindly.

    “All PCR experiments and western blot analyses for detecting transcript and protein levels were repeated at least twice independently and blindly.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Many studies have declared that apoptosis increases in the hypothalamus especially in the acute phase after TBI.

    “Many studies have declared that apoptosis increases in the hypothalamus especially in the acute phase after TBI (Chen et al. 2011;Tan et al. 2017).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Chen et al. 2011

      Not checked in the free run.

    • cites Tan et al. 2017

      Not checked in the free run.

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

    Study design and conductnone given

    All PCR experiments were repeated twice.

    “All PCR experiments were repeated twice.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Tan et al. (2017) developed an intracranial hypertension model and found that 24-hour intracranial hypertension increased the rate of apoptosis, particularly in the hypothalamus and pituitary.

    “Tan et al. developed an intracranial hypertension model to investigate its effects on the HPA axis caused by TBI.They found that 24-hour intracranial hypertension increased the rate of apoptosis, particularly in the hypothalamus and pituitary (Tan et al. 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Tan et al. 2017

      Not checked in the free run.

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

    Study design and conductnone given

    The male rats were randomly divided into three groups.

    “The male rats were randomly divided into three groups, and each group included 14 rats.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    An increased ratio of apoptosis in the adrenals in the acute phase may disrupt communication throughout the HPA axis and lead to permanent damage in the pituitary in the chronic phase.

    “In addition, an increased ratio of apoptosis in the adrenals in the acute phase may also disrupt communication throughout the HPA axis and lead to permanent damage in the pituitary in the chronic phase.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Chen et al. (2011) created TBI in rats using the fluid percussion injury model and found that the rate of apoptosis increased in the hypothalamus and pituitary in the 7th and 14th days after TBI.

    “In 2011, Chen et al. created TBI in rats using the fluid percussion injury model and found that the rate of apoptosis increased in the hypothalamus and pituitary in the 7th and 14th days after TBI (Chen et al. 2011).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Chen et al. 2011

      Not checked in the free run.

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

    Interpretationown data

    The transient increase in apoptosis during the acute phase after TBI in the adrenal may correspond to an active regenerative process in the tissues.

    “The transient increase in apoptosis during the acute phase after TBI in the adrenal may correspond to an active regenerative process in the tissues.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    β-Actin was used as a loading control.

    “β-Actin was used as a loading control.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    All western blot analyses were independently repeated at least twice.

    “All western blot analyses were independently repeated at least twice.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Autophagy is activated post-TBI.

    “Previous studies have demonstrated that autophagy is activated post-TBI, and the investigators thought that inhibition of the autophagic pathway might improve neurological deficits (Clark et al. 2008;Gao et al. 2017;Zhang and Wang 2018).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Clark et al. 2008

      Not checked in the free run.

    • cites Gao et al. 2017

      Not checked in the free run.

    • cites Zhang and Wang 2018

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    TBI seems to trigger apoptosis by inducing inflammation that can also affect the adrenals in the acute phase.

    “TBI seems to trigger apoptosis by inducing inflammation that can also affect the adrenals in the acute phase; and this situation may lead to an impairment of communication through the hypothalamus, pituitary and adrenal glands.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Adrenals are not directly affected by TBI.
34 of 34

  • The paper relies on this without support.

    The role of autophagy and apoptosis in the emergence of HPA axis dysfunction after TBI is not known.

    “The role of autophagy and apoptosis in the emergence of HPA axis dysfunction after TBI is not known.”

  • The paper relies on this without support.

    Adrenals are not directly affected by TBI.

    “Although adrenals are not directly affected by TBI, we suggest that the role of the adrenals together with the hypothalamus and pituitary should not be ignored in the acute phase after TBI.”

  • The paper relies on this without support.

    Endocrine dysfunctions after TBI have been clinically described in all hypothalamic-pituitary axes.

    “Endocrine dysfunctions after TBI have been clinically described in all hypothalamicpituitary axes.”

  • The paper relies on this without support.

    No studies in the literature have investigated the response and situation of the adrenal after TBI.

    “To date, no studies in the literature have investigated the response and situation of the adrenal after TBI, therefore, more investigation is required on this issue which could provide information to prevent consequences from secondary injury.”

  • The paper relies on this without support.

    The adrenal glands are not directly affected by TBI.

    “Although adrenals are not directly affected by TBI, we suggest that the role of the adrenal glands together with the hypothalamus and pituitary should not be ignored in the acute phase after TBI.”

  • The paper relies on this without support.

    The HPA axis is responsible for providing an adequate cortisol response to maintain homeostasis in stressful situations, such as TBI.

    “The HPA axis is responsible for providing an adequate cortisol response to maintain the homeostasis of organisms in stressful situations, such as TBI.”
6 of 6

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.

  • Abstract describes persistent adrenal decreases that discussion calls acute-only

    Major

    The abstract says adrenal P150 and Atg5 transcripts decline from the acute to chronic phase, while the discussion says their adrenal decrease occurred only in the acute phase.

  • Different p-values for the same adrenal Ulk comparison

    Minor

    The acute-phase adrenal Ulk decrease relative to sham is reported with two different p-values.

  • Claim that autophagy transcripts are lower in all tissues conflicts with adrenal Bcln1

    Minor

    The discussion describes autophagy-marker transcripts as significantly lower in all tissues, especially in the chronic phase, but the results report increased adrenal Bcln1 in that phase.

  • Section heading denies reported transcript changes

    Minor

    The heading says autophagy-marker transcripts did not change, whereas the results report significant decreases in P150 and Atg5 transcripts.

  • Conflicting total numbers of rats used

    Minor

    The methods state that 27 male rats were used, but elsewhere report 42 rats, divided into three groups of 14.

  • Contribution statement names mice instead of rats

    Minor

    The contribution statement says tissue was collected from mice, whereas the animal methods state that the study used rats.

6 of 6

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Simon DW, McGeachy M, Bayir H, et al (2017) Neuroinflammation in the Evolution of Secondary Injury, Repair, and Chronic Neurodegeneration after Traumatic Brain Injury. Nat Rev Neurol 13:171-191. https://doi.org/10.1038/nrneurol.2017. · DOI

Cited by

Sorted by citations

Related

Authors
Taheri, S., Karaca, Z., Mehmetbeyoglu, E., Hamurcu, Z., Yılmaz, Z., Dal, F., Cınar, V., Ulutabanca, H., Tanriverdi, F., Unluhizarci, K., Rassoulzadegan, M., & Kelestimur, F.
Affiliations
  • Erciyes University (TR)
  • Erciyes Universitesi Tip Fakultesi
  • Cardiff University School of Medicine
  • Centre National de la Recherche Scientifique (FR)
  • Yeditepe University School of Medicine: Yeditepe Universitesi Tip Fakultesi
ORCID
Venue
International Journal of Molecular Sciences
Publisher
Springer Science and Business Media LLC
Published
2022-02-01
Volume
23
Issue
24
Pages
15699-15699
ISSN
1422-0067 (ISSN-L)
DOI
10.21203/rs.3.rs-1159219/v1
PMC
PMC9778890
OpenAlex
W4312124036
Cited by
26
References
38
Citations by year
2026: 2 · 2025: 13 · 2024: 8 · 2023: 2 · 2022: 1
FWCI
3.16
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Erciyes Üniversitesi (TOA-2017-6994)
Topics
  • Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
Keywords
traumatic brain injury, hypothalamic-pituitary-adrenal axis, apoptosis, autophagy, neuroendocrine dysfunction, hypopituitarism, adrenal insufficiency, controlled cortical impact, caspase-3, LC3, ATG5, gene expression
MeSH terms
Brain Injuries, Traumatic, Animals, Autophagy, Hypothalamo-Hypophyseal System, Inflammation, Pituitary-Adrenal System, Apoptosis, Rats

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Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.

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