Disruption of Bax Protein Prevents Neuronal Cell Death but Produces Cognitive Impairment in Mice following Traumatic Brain Injury

Tehranian, Roya; Rose, Marie E.; Vagni, Vincent; Pickrell, Alicia M.; Griffith, Raymond P.; Líu, Hao; Clark, Robert S. B.; Dixon, C. Edward; Kochanek, Patrick M.; Graham, Steven H.

doi:10.1089/neu.2007.0441

Cited by 54 publications

(37 citation statements)

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“…Mechanical disruption of neurons triggers a cascade of events leading to neuronal cell death following TBI (2). Apoptosis has been attributed to programmed neuronal cell death in TBI (3). Notably, previous studies have also shown that autophagy is increased following TBI (4).…”

Section: Introductionmentioning

confidence: 99%

Astrocytic p-connexin 43 regulates neuronal autophagy in the hippocampus following traumatic brain injury in rats

Gao

Cui

et al. 2013

Molecular Medicine Reports

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Abstract. Gap junctions are conductive channels formed by membrane proteins termed connexins, which permit the intercellular exchange of metabolites, ions and small molecules. Previous data demonstrated that traumatic brain injury (TBI) activates autophagy and increases microtubule-associated protein 1 light chain 3 (LC3) immunostaining predominantly in neurons. Although previous studies have identified several extracellular factors that modulate LC3 expression, knowledge of the regulatory network controlling LC3 in health and disease remains incomplete. The aim of the present study was to assess whether gap junctions control the in vivo expression of LC3 in TBI. Using a modified weight-drop device, adult male Sprague-Dawley rats (weight, 350-375 g) were subjected to TBI. Phosphorylated gap junction protein levels and LC3-Ⅱ levels were quantified using western blot analysis. The spatial distribution of immunoreactivity for phosphorylated connexin 43 (p-CX43) and LC3-Ⅱ was analyzed by immunofluorescence. The results showed that p-CX43 expression in the hippocampus reached a maximum level 6 h following injury. In addition, the immunoreactivity of p-CX43 was localized in the astrocytes surrounding pyramidal neurons. The LC3-Ⅱ protein content remained at high levels 24 h following injury. Double immunolabeling demonstrated that LC3-II dots colocalized with the hippocampus pyramidal neurons. Furthermore, inhibition of p-CX43 reduced TBI-induced autophagy, according to western blot analysis. As astrocytic gap junction coupling is affected in various forms of brain injury, the results suggest that point gap junctions/connexins are important regulators of autophagy in the hippocampal neurons following TBI.

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Section: Introductionmentioning

confidence: 99%

Astrocytic p-connexin 43 regulates neuronal autophagy in the hippocampus following traumatic brain injury in rats

Gao

Cui

et al. 2013

Molecular Medicine Reports

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“…We noted a spectrum of functional deficits rarely seen when CCI is studied alone (Abrahamson et al, 2009;Smith et al, 1995;Tehranian et al, 2006Tehranian et al, ,2008Whalen et al, 1999aWhalen et al, ,1999bYou et al, 2008). We chose a mild to moderate CCI to limit functional deficits and neuropathology due to CCI alone, so that the full impact of secondary HS could be revealed.…”

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confidence: 99%

Severe Brief Pressure-Controlled Hemorrhagic Shock after Traumatic Brain Injury Exacerbates Functional Deficits and Long-Term Neuropathological Damage in Mice

Hemerka

Dixon

et al. 2012

Journal of Neurotrauma

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Hypotension after traumatic brain injury (TBI) worsens outcome. We published the first report of TBI plus hemorrhagic shock (HS) in mice using a volume-controlled approach and noted increased neuronal death. To rigorously control blood pressure during HS, a pressure-controlled HS model is required. Our hypothesis was that a brief, severe period of pressure-controlled HS after TBI in mice will exacerbate functional deficits and neuropathology versus TBI or HS alone. C57BL6 male mice were randomized into four groups (n = 10/group): sham, HS, controlled cortical impact (CCI), and CCI + HS. We used a pressure-controlled shock phase (mean arterial pressure [MAP] = 25-27 mm Hg for 35 min) and its treatment after mild to moderate CCI including, a 90 min pre-hospital phase, during which lactated Ringer's solution was given to maintain MAP > 70 mm Hg, and a hospital phase, when the shed blood was re-infused. On days 14-20, the mice were evaluated in the Morris water maze (MWM, hidden platform paradigm). On day 21, the lesion and hemispheric volumes were quantified. Neuropathology and hippocampal neuron counts (hematoxylin and eosin [H&E], Fluoro-Jade B, and NeuN) were evaluated in the mice (n = 60) at 24 h, 7 days, or 21 days (n = 5/group/time point). HS reduced MAP during the shock phase in the HS and CCI + HS groups ( p < 0.05). Fluid requirements during the pre-hospital phase were greatest in the CCI + HS group ( p < 0.05), and were increased in HS versus sham and CCI animals ( p < 0.05). MWM latency was increased on days 14 and 15 after CCI + HS ( p < 0.05). Swim speed and visible platform latency were impaired in the CCI + HS group ( p < 0.05). CCI + HS animals had increased contusion volume versus the CCI group ( p < 0.05). Hemispheric volume loss was increased 33.3% in the CCI + HS versus CCI group ( p < 0.05). CA1 cell loss was seen in CCI + HS and CCI animals at 24 h and 7 days ( p < 0.05). CA3 cell loss was seen after CCI + HS ( p < 0.05 at 24 h and 7 days). CA1 cell loss at 21 days was seen only in CCI + HS animals ( p < 0.05). Brief, severe, pressure-controlled HS after CCI produces robust functional deficits and exacerbates neuropathology versus CCI or HS alone.

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“…Unlike the Bid-/-and previous Bax-/-studies, injuryinduced caspase-3 expression within the cortex or hippocampus did not differ between Bax null and wild-type mice, although Bax null mice did not exhibit the post-traumatic nuclear translocation of activated caspase-3 observed in wild-type mice. Despite a reduction in numbers of TUNEL+ cells with apoptotic morphology within the dentate gyrus and CA1 regions of the hippocampus 24 h after CCI, only small, nonsignificant decreases in cortical lesion size or CA1 and CA3 neuronal death were noted [38]. Importantly, uninjured Bax null mice had significantly larger brain size and CA1 neuronal cell numbers compared to wild-type mice, consistent with abnormal developmental pruning through apoptosis.…”

Section: Bcl-2 Family (Bid Bax)mentioning

confidence: 85%

“…AIF0apoptosis-inducing factor; CypA0cyclophilin A; DFF=DNA fragmentation factor; PARP0poly(ADPribose) polymerase mice [37]. A second study sought to confirm acute changes in cell survival after CCI injury in Bax null mice [38]. Unlike the Bid-/-and previous Bax-/-studies, injuryinduced caspase-3 expression within the cortex or hippocampus did not differ between Bax null and wild-type mice, although Bax null mice did not exhibit the post-traumatic nuclear translocation of activated caspase-3 observed in wild-type mice.…”

Section: Bcl-2 Family (Bid Bax)mentioning

confidence: 99%

“…Importantly, uninjured Bax null mice had significantly larger brain size and CA1 neuronal cell numbers compared to wild-type mice, consistent with abnormal developmental pruning through apoptosis. Inhibition of Bax-dependent developmental apoptosis may underlie behavioral deficits observed in Bax null mice compared to wild-type counterparts, regardless of injury [38]. Because the CCI impactor tip was not scaled for the larger Bax null mouse brain, Bax null mice likely received a milder injury than did wild-type mice.…”

Section: Bcl-2 Family (Bid Bax)mentioning

confidence: 99%

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Genetic Manipulation of Cell Death and Neuroplasticity Pathways in Traumatic Brain Injury

2012

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Traumatic brain injury (TBI) initiates a complex cascade of secondary neurodegenerative mechanisms contributing to cell dysfunction and necrotic and apoptotic cell death. The injured brain responds by activating endogenous reparative processes to counter the neurodegeneration or remodel the brain to enhance functional recovery. A vast array of genetically altered mice provide a unique opportunity to target single genes or proteins to better understand their role in cell death and endogenous repair after TBI. Among the earliest targets for transgenic and knockout studies in TBI have been programmed cell death mediators, such as the Bcl-2 family of proteins, caspases, and caspaseindependent pathways. In addition, the role of cell cycle regulatory elements in the posttraumatic cell death pathway has been explored in mouse models. As interest grows in neuroplasticity in TBI, the use of transgenic and knockout mice in studies focused on gliogenesis, neurogenesis, and the balance of growth-promoting and growth-inhibiting molecules has increased in recent years. With proper consideration of potential effects of constitutive gene alteration, traditional transgenic and knockout models can provide valuable insights into TBI pathobiology. Through increasing sophistication of conditional and cell-type specific genetic manipulations, TBI studies in genetically altered mice will be increasingly useful for identification and validation of novel therapeutic targets.

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Disruption of Bax Protein Prevents Neuronal Cell Death but Produces Cognitive Impairment in Mice following Traumatic Brain Injury

Cited by 54 publications

References 50 publications

Astrocytic p-connexin 43 regulates neuronal autophagy in the hippocampus following traumatic brain injury in rats

Astrocytic p-connexin 43 regulates neuronal autophagy in the hippocampus following traumatic brain injury in rats

Severe Brief Pressure-Controlled Hemorrhagic Shock after Traumatic Brain Injury Exacerbates Functional Deficits and Long-Term Neuropathological Damage in Mice

Genetic Manipulation of Cell Death and Neuroplasticity Pathways in Traumatic Brain Injury

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