Traumatic Brain Injury

Traumatic Brain Injury
Image Unavailable
Primary traumatic brain injury, resulting from a direct blow to the head

Traumatic brain injury (TBI) has profound effects on the brain and is a major concern to health care worldwide. TBI can arise from pressure applied to the brain in the form of a direct blow to the head or objects being lodged in the skull[25]. The major causes of TBI are vehicle accidents and sports injuries; the latter possibly affecting developing brains. Understanding the outcomes of TBI in sports injuries may aid: the diagnosis process and the development of treatment options.

Depending on the severity of the head injury acute responses such as inflammation and microenvironment modifications have been reported[25]. To further understand the cortical changes that occur shortly after TBI, cellular processes that lead to vascular changes and upregulation of toxic molecules have been closely monitored. These alterations within the neocortex may also be driven by gene expression; therefore possible treatments to mitigate the consequences of TBI could target gene expression via pharmacokinetics or stem cell therapy.

1.0 Microenvironment Changes

Traumatic brain injury (TBI) causes structural changes within the brain that can be identified using various imaging techniques, microdialysis and angiography[25]. Furthermore we can understand the physiology behind structural changes to identify microenvironment changes such as cell death, changes in blood flow, brain temperature and the accumulation of toxic compounds.

Microenvironment Changes
Image Unavailable
Physical and chemical changes observed post TBI Park et al. (2008)

1.1 Cell Death and Toxic Compounds

Cell death is often coupled with brain injuries. Depending on where in the neocortex cell death occurs functional impairment maybe observed. Glycogen synthase kinase 3 (GSK-3), which regulates glycogen metabolism, protein synthesis, and cell differentiation, is thought to be involved in apoptosis following TBI[21]. GSK-3 leads to the accumulation of beta-catenin via WNTS signalling[17]. The activated signaling pathway causes cell death via gene expression of pro-apoptotic factors[17]. Cell death although a local process, has an effect on the neighbouring environment.

Once a cell lyses or dies it can release inflammatory factors, cytokines, chemokines, proteases and reactive oxygen species(ROS), which are toxic to neurons[7]. Plasticity and cognition are affected in the presence of ROS[1], [4]. Cell death decreases in NR2A subunits of glutamate receptor, known to be involved in long-term potentiation (LTP) [25], an important molecular process in plasticity and learning. Microglia are recruited to mitigate cellular damage but release inflammatory molecueles such as tumor necrosis factor-alpha (TNF-α) [16]. Accumulation of water in the extracellular space and vasoconstriction due to vasospasm are linked to increases in TNF-α[22], [29]. Upregulation of TNF-α receptor also leads to cell death, but different from the ROS/mitochondrial mediated pathway.

1.2 Vascular Changes

TBI perturbs vascular homeostasis within the brain and the blood brain barrier (BBB). Low cerebral perfusion (CCP) and decreases in brain tissue oxygenation have been documented in human and animal models post TBI[24]. The lack of oxygen will lead to loss of vasculature and cerebral blood flow (CBF) [25]. Response proteins are quickly synthesized to combat the hypoxic area, which was modeled in rats that sustained fluid percussion related TBI[35]. Therefore secondary hypoxia and ischemic damage could contribute to the physiology of TBI[35]. Researchers have extensively looked at two candidates that contribute to vascular changes following TBI. The canonical view is that there is an upregulation of endothelin-1 synthesis, which is vasoconstrictor, reducing blood flow at the site of injury[39]. The second, recent finding suggests that damage may activate the thrombogenesis pathway[38]. The BBB serves to protect the neocortex from toxic compounds and regulates the flow of nutrients. Analysis of post blast TBI rats indicates that the BBB is sensitive to degradation induced by the destruction of astrocyte feet and capillaries[30]. Disruptions in barrier function could lead to the accumulation of toxic compounds and an imbalance of nutrients further adding to the severity of the injury.

1.3 Brain Temperature

TBI on the Different Lobes of the Brain
Possible microenvironment changes may lead to cognitive and functional outcomes

Changes in brain temperature have been associated with traumatic brain injury[12]. Elevated brain temperatures have been linked to the increased risk of incurring a secondary insult, whereas hypothermia results in decreases in pyruvate and lactic acid[43]. Lower levels of pyruvate and lactic acid suggest a bio-energetic deficiency associated with brain temperature as a result of TBI[25]. Researchers have also identified metabolic imbalance due to hypothermia associated with increased glutamate, calcium, inflammation and the breakdown of the blood brain barrier[37].

2.0 Genetics in TBI

Gene expression and genetics play a significant role in the physiology of TBI. Gene-expression pattern and specific genotypes may provide insight about the severity of the injury and the ability to recover. Specific receptors are transiently activated after TBI and can either serve as a neuroprotectant or aid in determining the severity of the injury.

2.1 Effects of Glutamate decarboxylase Gene

Darrah et al. documented the importance of inhibition in individuals that have sustained TBI using gamma-Aminobutyric acid (GABA) as a model[15]. The glutamate de-carboxylase (GAD) gene product is vital in the synthesis pathway of GABA, an inhibitory neurotransmitter[28]. GABA is often depleted in TBI while glutamate remains at high levels; this imbalance leads to seizures[26], [34]. The researchers evaluate the effects of single nucleotide polymorphisms (SNPs) in specific GAD genes in relation to the likelihood of incurring seizures post TBI. The GAD 1 gene with the polymorphisms rs3791878 (GG genotype) and rs769391 (AA genotype) saw a risk for seizures 1 week to 6 months post injury[15]. The rs3791878 polymorphism is associated with transcriptional deficiency of the GAD gene, leading to a dysfunctional gene product[15]. Binding sites within the promoter region for aryl hydrocarbon receptor nuclear translocator (ARNT) and x-box binding protein (XBP1) are eliminated[18]. These proteins are part of the immune response and anti-inflammatory pathways, activated during injury[36], [46]. The variability in the GAD gene may help identify individuals susceptible to seizures post TBI.

2.2 Upregulation of Voltage Gated Sodium Channels and Metabotropic Glutamate Receptor

Voltage gated sodium channels (VGSCs) are responsible for Na+ influx during hypoxia and ischemia and certain isoforms are known to contribute to epilepsy in mammals[8]. Findings by Huang et al. suggest that expression levels of VGSC Nav 1.3 in the hippocampus are associated with the severity of TBI[23]. Rats were subject to mild and severe TBI using fluid percussion device at different pressures (measured in Atm)[23]. In the group that underwent severe TBI there was an increase in Nav 1.3 when compared to results from the mild TBI group[23]. The differential expression of Nav 1.3 may predict the severity of the injury and also account for post TBI seizures due to the transient increase of sodium influx[23]. Nav 1.6, functionally similar to Nav 1.3, also shows an increase in expression[32]. Although there is an increase in Nav 1.6 there is no established correlation between expression levels and the severity of TBI. Understanding the underlying expression patterns of specific voltage gated sodium channels may provide an opportunity to develop effective treatments.

Increased expression of certain genes, such as metabotropic glutamate receptor 5 (mGluR5), may also serve neuroprotective functions. Unlike ionotropic glutamate receptors,mGluRs do not contribute to excitotoxcity by excess glutamate release[19]. TBI induced rats showed increased mGLuR5 mRNA and protein when compared to a sham control group[42]. Immunochemistry assays suggest that prior to TBI, mGLuR5 is concentrated at the nucleus and quickly mobilized to the plasma membrane following injury[42]. (RS)-2-chloro-5-hydroxyphenylglycine (CHPG), an mGluR5 agonist, has shown to inhibit apoptosis, promote neurogenesis and reduce the size of the lesion area[9], [10], [45]. The levels of mGluR5 are elevated in vivo up to 24 hours post TBI suggesting limited neuroprotective effects.

2.3 Apoplipoprotein Prediciting Outcome of TBI

Apoliprotein Expression
Image Unavailable
The quantitative expression pattern of APOE genotypes in TBI (Crawford et al 2009)

Apolipoprotein E (APO) genotypes have been associated with dementia in Down syndrome and Alzheimer's disease (AD)[27]. There are three isofroms, APOE2, APOE3 and APOE4, with the APOE4 genotype being the greatest risk for AD and poor recovery from brain injuries such as TBI[31], [41]. Crawford and colleagues reported several different gene expression changes related to the APOE3 and APOE4 genotypes in the hippocampus and cortex of TBI rats[14]. In mice the E3 genotype saw 621 genes upregulated where as 86 were down regulated, in contrast the E4 had 207 and 74 respectively[14]. The APOE3 genotype is associated with genes such as C-type lectin domain family 7 (CLEC7A), lipocalin 2 (LPN2) which are increased in expression and promote anti-inflammatory, and pro-immune responses[14]. For the APOE4 phenotype there is a decrease in WNT2 and granulin (GRN) expression, genes that are thought to be pro-neurogenic[11], [33]. The APOE4 genotype has shown to alter blood flow via cyclophillin A. Cyp-A activates the nuclear factor kappa B and metalloproteinases, which cleave extracellular matrices (ECMs) [39]. The ECMs surrounding astrocytes, which make up the BBB are susceptible to degradation based on the APOE4 genotype and the activation of the Cyp-A pathway[5] On the other hand the pro-neurogenic genes are upregulated in groups that have the APOE3 phenotype[14]. This suggests that the APOE3 phenotype might educe better neurogenerative properties than APOE4. Given the dependence for genotype-mediated response to injury, individuals possessing the E3 genotype may recover better from sustained brain damage.

3.0 Treatment Options

With knowledge about the specific structural changes, how genes and genetics play a role in the physiology of TBI there is promise in developing treatment options to reduce severe functional outcomes of TBI. Options include stem cell transplants as well as combating energy deficits post TBI through dinucleotide administration.

3.1 Stem Cell Transplants

Morris Water Maze Test
Image Unavailable
Spatial and learning memory is unaffected in groups that incurred TBI with NC/NPCs transplants when compared to controls (Sun et al 2011)

Based on the principle that cell transplants can adapt to their environment through differentiation, they could replace dead cells at the site of injury. These cells could aid host cells in the recovery process by secreting growth factors and neurotransmitters[6], [20]. Neural stem cells (NS) and neural progenitor cells (NPC) are found in the subventricular zone and have the potential to differentiate based on signaling, and the surrounding environment[3]. Sun et al. transplanted NC/NPCs into the damaged area of rats, and after sacrificing the animals the immunoassayed cells survived at 2 and 4 weeks[43]. Some of the cells exhibited biomarkers of oligodendroycites and astrocytes[40]. Astrocytes are essential for the BBB; therefore using NC/NPCs transplantation can help maintain the integrity of the BBB post TBI to minimize neurotoxicity. Although a promising therapeutic solution to TBI, complications arise due to immune response raised by the graft and the short life span of the transplanted cells[40].

3.2 Nicotinamide Dinucleotide Intranasal Spray

A non-toxic putative treatment for TBI is using nicotinamide dinucleotide (NAD) to prevent cell death due to brain injury. Cortex insults lead to an increase in poly (ADP-ribose) polymerases (PARPs) resulting to a depletion of NAD, a molecule important for generating adenosine triphosphate (ATP) [2]. The lack of ATP eventually leads to cell death via release of apoptosis inducing factor (AIP) from the mitochondrion[2]. Rats were administered NAD after sustaining damage to the cortex and hippocampus. In the hippocampus cells did not undergo cell death, although the same effect was not observed in the cortex[44]. NAD was also found to reduce microglial activation, which is responsible for inflammatory responses[44]. Using NAD treatment may help in reducing functional deficits as a result of brain injury. Preventing apoptosis in the hippocampus will preserve spatial learning and memory in the event of TBI, which was tested using the Morris water maze test in brain injured rats[13]. Present work has only shown the effectiveness of NAD within the hippocampus, not the cortex, consequently physiological effects of NAD in the cortex need to be fully elucidated[44].

4.0 The Future of TBI

TBI effects Long Term
Image Unavailable
Concussions are the leading cause of TBI in sports. Repeated concussions can permanently alter the cortex leading to complications in near or far future  

Traumatic brain injury whether modeled in humans or mice provides insight into the dynamic modifications that occur within the brain. Depending on the severity of TBI microenvironment changes can be visualized and used to predict cognitive and functional outcomes. As the field of study progresses there is a need to understand how cortical changes lead to long-term deficits. The acute damage mediated by cell death, brain temperature and alterations in blood flow may lead to further complications and disease such as chronic-traumatic-encephalopathy (CTE).

Gene expression patterns are inherently linked TBI. Monitoring mutations, upregulation, downregulation and genotyping may explicate the severity of the injury, the susceptibility to seizures, and the ability to recover from the injury. Coupling the knowledge about genetic and cortical modifications may lead to promising treatments for TBI to reduce the localized damage and improve recovery. The list of treatment options for TBI patients is a short one, therefore the more we delve into the dynamics of genetics on structure and function many avenues may become available for therapy.

See also

  1. Methods in Concussion Detection and Assessment
  2. Dr. Morshead's papers regarding stem cells
  3. Sports Related TBI
  4. Behavioural Changes in TBI
Bibliography
1. Aiguo W, Zhe Y, Gomez-Pinilla F (2010) Vitamin E protects against oxidative damage and learning disability after mild traumatic brain injury in rats. Neurorehabil. Neural Repair (24): 290–298.
2. Alano C.C, Garnier P, Ying W, Higashi Y, Kauppinen T.M, Swanson R.A (2010). NAD + depletion is necessary and sufficient for poly (ADP-ribose) polymerase-1- mediated neuronal death. J. Neurosci. (30): 2967–2978
3. Altman J, Das G.D (1965). Autoradiographic and histo- logical evidence of postnatal hippocampal neurogenesis in rats. J. Comp. Neurol. (124): 319–335.
4. Bayir H, Kagan V.E, Clark R.S, Janesko-Feldman K, Rafikov R, Huang Z, Zhang X, Vagni V, Billiar T.R, Kochanek P.M (2007) Neuronal NOS-mediated nitration and inactivation of manganese superoxide dismutase in brain after experimental and human brain injury. J. Neurochem. (101): 168–181.
5. Bell R.D, Winkler E.A, Singh I, Sagare A.P, Deane R, Wu Z, Holtzman D.M, Betsholtz C, Armulik A, Sallstrom J, Berk B.C, Zlokovic B.V (2012). Apolipoprotein E controls cerebrovasuclar integrity via cyclophilin A (485): 512-516.
6. Bjorklund A, Kirik D, Rosenblad C, Georgievska B, Lundberg C, and Mandel R.J (2000). Towards a neuroprotective gene therapy for Parkinson’s disease: use of adenovirus, AAV and lentivirus vectors for gene transfer of GDNF to the nigrostriatal system in the rat Parkinson model. Brain Res. 886, 82–98.
7. Cai A.L, Zipfel, G.J, Sheline, C.T. (2006). Zinc neurotox- icity is dependent on intracellular NAD levels and the sirtuin pathway. Eur. J. Neurosci. (24): 2169–2176.
8. Catterall W.A, Goldin A.L, Waxman S.G (2005). International Union of Pharmacology. XLVII. Nomenclature and structure–function relationships of voltage-gated sodium channels. Pharmacol. Rev. (57): 397-409.
9. Chen T, Cao L, Dong W, Luo P, Liu W, Qu Y, Fei Z, (2012). Protective effects of mGluR5 positive modulators against traumatic neuronal injury through PKC-dependent activation of MEK/ERK pathway. Neurochem. Res. (37): 983–990.
10. Chen, T, Zhang L, Qu Y, Huo K, Jiang X, Fei Z, (2012). The selective mGluR5 agonist CHPG protects against traumatic brain injury in vitro and in vivo via ERK and Akt pathway. Int. J. Mol. Med. (29): 630–636.
11. Chiba S, Suzuki M, Yamanouchi K, Nishihara M (2007). Involvement of granulin in estrogen-induced neurogenesis in the adult rat hippocampus. J Reprod Dev (53): 297–307.
12. Childs C, Vail A, Leach P, Rainey T, Protheroe R, King A. (2006) Brain temperature and outcome after severe traumatic brain injury, Neurocrit. Care (5): 10–14.
13. Clark R.S, Vagni V.A, Nathaniel P.D, Jenkins L.W, Dixon C.E, Szabo C (2007). Local administration of the poly (-ADP-ribose) polymerase inhibitor INO-1001 prevents NAD + depletion and improves water maze performance after traumatic brain injury in mice. J. Neurotrauma 24, 1399–1405.
14. Crawford F, Wood M, Ferguson S, Mathura V, Gupta P, Humphrey J, Mouzon B, Laporte V, Margenthaler E, O’Steen B, Hayes R, Roses A, Mullan M (2009). Apolipoprotein E-Genotype dependant hippocampal and cortical responses to traumatic brain injury. Neuroscience (159): 1349-1362.
15. Darrah S.D, Miller M.A, Ren D, Hoh N.Z, Scanlon J.M, Conley Y.P, Wagner A.K (2012). Genetic variability in glutamic acid decarboxylase genes: Associations with post-traumatic seizures after severe TBI. Epilepsy Research (103): 180-194
16. Das M, Leonardo C.C, Rangooni S, Pennypacker K.R, Mohapatra S, Mohapatra S.S (2011). Lateral Fluid Percussion Injury of the brain induces CCL20 inflammatory chemokine expression in rats. J. Neuroinflammation (8): 148.
17. Dash P.K, Johnson D, Clark J, Orsi S.A, Zhang M, Zhao J, Grill R.J, Moore A.N, Pati S (2011) Involvement of Glycogen Synthase Kinase -3 Signaling Pathway in TBI Pathology and Neurocognitive Outcome. PLoS ONE (6): e24648
18. Du, J, Duan S, Wang H, Chen W, Zhao X, Zhang A, Wang L, Xuan J, Yu L, Wu S, Tang W, Li X, Li H, Feng G, Xing Q, He L, (2008). Comprehensive analy- sis of polymorphisms throughout GAD1 gene: a family-based association study in schizophrenia. J. Neural Transm. (115): 513-519.
19. Faden, A, Demediuk, P, Panter, S, Vink R, (1989). The role of excitatory amino acids and NMDA receptors in traumatic brain injury. Science (244): 798–800.
20. Gage F.H, Coates P.W, Palmer T.D, Kuhn H.G, Fisher L.J, Suhonen J.O, Peterson D.A, Suhr S.T, and Ray, J (1995). Survival and differentiation of adult neuronal progenitor cells transplanted to the adult brain. Proc. Natl. Acad. Sci. USA (92): 11879–11883.
21. Grimes C.A, Jope R.S (2001) The multifaceted roles of glycogen synthase kinase 3beta in cellular signaling. Prog Neurobiol (65): 391–426.
22. Hanafy A, Stuart R.M, Khandji A.G, Connolly E.S, Badjatia N, Mayer S.A, Schindler C (2010). Relationship between brain interstitial fluid tumor necrosis factor- alpha and cerebral vasospasm after aneurysmal subarachnoid hemorrhage. J. Clin. Neurosci. (17): 853–856.
23. Huang X, Mao Q, Lin Y, Feng J, Jiang J, (2013). Expression of Voltage-Gated Sodium Channel Nav1.3 Is Associated with Severity of Traumatic Brain Injury in Adult Rats. J. Neurotrauma. (30): 39-46.
24. Jaeger M, Dengl M, Meixensberger J, Schuhmann M.U (2010) Effects of cerebrovascular pressure reactivity-guided optimization of cerebral perfusion pressure on brain tissue oxygenation after traumatic brain injury. Crit. Care Med. (38): 1343–1347.
25. Kan E.M, Ling E.A, Lu J (2012). Microenvironment changes in mild traumatic brain injury. Brain Research Bulletin (87): 359-372.
26. Kanthan R, Shuaib A, (1995). Clinical evaluation of extracellular amino acids in severe head trauma by intracerebral in vivo microdialysis. J. Neurol. Neurosurg. Psychiatry (59): 326-327.
27. Kim J, Basak J.M, Holtzman D. M (2009) The role of apolipoprotein E in Alzheimer’s disease. Neuron (63): 287–303.
28. Kuo P.H, Kalsi, G, Prescott, C.A, Hodgkinson, C.A, Goldman, D, Alexander, J, van den Oord E.J, Chen X, Sullivan P.F, Patterson D.G, Walsh D, Kendler K.S, Riley B.P, (2009). Associations of glutamate decarboxylase genes with initial sensitivity and age-at-onset of alcohol dependence in the Irish affected Sib Pair Study of Alcohol Dependence. Drug Alcohol Depend. (101): 80-87.
29. Lenzlinger P.M, Morganti-Kossmann M.C, Laurer H.L, McIntosh T.K (2001) The duality of the inflammatory response to traumatic brain injury, Mol. Neurobiol. (24): 169–181.
30. Lu J, Ng K.C, Ling G.S, Wu J, Poon J.F, Kan E.M, Tan H.M, Wu Y.J, Li P, Moochhala S, Yap E, Lee L.K, Teo A.L, Yeh I.B, Sergio D.M, Chua F, Kumar S.D, Ling E.A (2012) Effect of blast exposure on the brain structure and cognition in the Macaca fascicularis, J. Neurotrauma (29): 1434-1454
31. Mahley R.W, Weisgraber K.H, Huang Y (2009). Apolipoprotein E: structure determines function, from atherosclerosis to Alzheimer’s disease to AIDS. J. Lipid Res. (50) (Suppl): S183–S188.
32. Mao Q, Feng J, Zhang X, Qiu Y, Ge J, Bao Wen, Luo Q, Jiang J (2010) The Up-Regulation of Voltage Gated Sodium Channel Nav1.6 Expression Following Fluid Percussion Traumatic Brain Injury in Rats. Neurosurgery (66): 1124-1139.
33. Morris DC, Zhang ZG, Wang Y, Zhang RL, Gregg S, Liu XS, Chopp M (2007). Wnt expression in the adult rat subventricular zone after stroke. Neurosci Lett (418): 170–174.
34. Nilsson P, Hillered L, Pontén U, Ungerstedt U (1990). Changes in cortical extracellular levels of energy-related metabolites and amino acids following concussive brain injury in rats. J. Cereb. Blood Flow Metab. (10): 631-637.
35. Park E, Bell J.D, Siddiq I.P, Baker A.J (2009). An analysis of regional microvascular loss and recovery following two grades of fluid percussion trauma: a role for hypoxia-inducible factors in traumatic brain injury. J. Cereb. Blood Flow Metab. (29): 575–584.
36. Ruegg J, Swedenborg E, Wahlstrom D, Escande A, Balaguer P, Pettersson K, Pongratz I, (2008). The transcription factor aryl hydrocarbon receptor nuclear translocator functions as an estrogen receptor beta-selective coactivator, and its recruitment to alternative pathways mediates antiestrogenic effects of dioxin. Mol. Endocrinol. (22): 304-316.
37. Sakurai A, Atkins C.M, Alonso O.F, Bramlett H.M, Dietrich W.D (2012). Mild hyperthermia worsens the neuropathological damage associated with mild traumatic brain injury in rats. J. Neurotrauma (29): 313–321.
38. Schwarzmaier S.M, Kim S.W, Trabold R, Plesnila N (2010). Temporal profile of thrombogenesis in the cerebral microcirculation after traumatic brain injury in mice. J. Neurotrauma (27): 121–130.
39. Steiner J, Rafols D, Park H.K, Katar H.S, Rafols J.A, Petrov T (2004) Attenuation of iNOS mRNA exacerbates hypoperfusion and upregulates endothelin-1 expression in hippocampus and cortex after brain trauma, Nitric Oxide (10): 162–169.
40. Sun D, Gugliotta M, Rolfe A, Reid W, McQuiston A.R, Hu W, Young H (2011). Sustain survival and maturation of adult neural stem/progenitor cells after transplantation into the injured brain. J. Neurotrauma (28): 961-972.
41. Verghese P.B, Castellano J.M Holtzman D. M (2011). Apolipoprotein E in Alzheimer’s disease and other neurological disorders. Lancet Neurol. (10): 241–252
42. Wang J, Wang H, Zhong W, Li N, Cong Z (2012). Expression and cell distribution of metabotropic glutamate receptor 5 in the rat cortex following traumatic brain injury. Brain Res. (1464): 73-81.
43. Wang Q, Li A.L, Zhi D.S, Huang H.L (2007) Effect of mild hypothermia on glucose metabolism and glycerol of brain tissue in patients with severe traumatic brain injury. Chin. J. Traumatol. (10): 246–249.
44. Won S.K, Choi B.Y, Yoo B.H, Sohn M, Weihai Y, Sawnson R.A, Suh S.W (2012). Prevention of traumatic brain injury-induced neuron death by intranasal delivery of nicotinamide adenine dinucleotide. J. Neurotrauma (29): 1401-1409.
45. Xu X, Zhang J, Chen X, Liu J, Lu H, Yang P, Xiao X, Zhao L, Jiao Q, Zhao B, Zheng P, Liu Y (2012). The increased expression of metabotropic glutamate receptor 5 in subventricular zone neural progenitor cells and enhanced neurogenesis in a rat model of intracerebral hemorrhage. Neuroscience. (202): 474–483.
46. Yoshida, H, Nadanaka S, Sato R, Mori K, (2006). XBP1 is critical to protect cells from endoplasmic reticulum stress: evidence from Site-2 protease-deficient Chinese hamster ovary cells. Cell Struct. Funct. (31): 117-125.
Add a New Comment
Unless otherwise stated, the content of this page is licensed under Creative Commons Attribution-ShareAlike 3.0 License