The PKR-like ER kinase (PERK), a transmembrane protein, resides in the endoplasmic reticulum (ER). Its activation serves as a key sensor of ER stress, which has been implicated in traumatic brain injury (TBI). The loss of memory is one of the most common symptoms after TBI, but the precise role of PERK activation in memory impairment after TBI has not been well elucidated. Here, we have shown that blocking the activation of PERK using GSK2656157 prevents the loss of dendritic spines and rescues memory deficits after TBI. To elucidate the molecular mechanism, we found that activated PERK phosphorylates CAMP response element binding protein (CREB) and PSD95 directly at the S129 and T19 residues, respectively. Phosphorylation of CREB protein prevents its interaction with a coactivator, CREB-binding protein, and subsequently reduces the BDNF level after TBI. Conversely, phosphorylation of PSD95 leads to its downregulation in pericontusional cortex after TBI in male mice. Treatment with either GSK2656157 or overexpression of a kinase-dead mutant of PERK (PERK-K618A) rescues BDNF and PSD95 levels in the pericontusional cortex by reducing phosphorylation of CREB and PSD95 proteins after TBI. Similarly, administration of either GSK2656157 or overexpression of PERK-K618A in primary neurons rescues the loss of dendritic outgrowth and number of synapses after treatment with a PERK activator, tunicamycin. Therefore, our study suggests that inhibition of PERK phosphorylation could be a potential therapeutic target to restore memory deficits after TBI.

Persistent endoplasmic reticulum (ER) stress in neurons is associated with activation of inflammatory cells and subsequent neuroinflammation following traumatic brain injury (TBI); however, the underlying mechanism remains elusive. We found that induction of neuronal-ER stress, which was mostly characterized by an increase in phosphorylation of a protein kinase R-like ER kinase (PERK) leads to release of excess interferon (IFN)␤ due to atypical activation of the neuronal-STING signaling pathway. IFN␤ enforced activation and polarization of the primary microglial cells to inflammatory M1 phenotype with the secretion of a proinflammatory chemokine CXCL10 due to activation of STAT1 signaling. The secreted CXCL10, in turn, stimulated the T-cell infiltration by serving as the ligand and chemoattractant for CXCR3 ϩ T-helper 1 (Th1) cells. The activation of microglial cells and infiltration of Th1 cells resulted in white matter injury, characterized by impaired myelin basic protein and neurofilament NF200, the reduced thickness of corpus callosum and external capsule, and decline of mature oligodendrocytes and oligodendrocyte precursor cells. Intranasal delivery of CXCL10 siRNA blocked Th1 infiltration but did not fully rescue microglial activation and white matter injury after TBI. However, impeding PERK-phosphorylation through the administration of GSK2656157 abrogated neuronal induction of IFN␤, switched microglial polarization to M2 phenotype, prevented Th1 infiltration, and increased Th2 and Treg levels. These events ultimately attenuated the white matter injury and improved anxiety and depressive-like behavior following TBI.

AbstractTraumatic brain injury (TBI), a major global health and socioeconomic problem, is now established as a chronic disease process with a broad spectrum of pathophysiological symptoms followed by long-term disabilities. It triggers multiple and multidirectional biochemical events that lead to neurodegeneration and cognitive impairment. Recent studies have presented strong evidence that patients with TBI history have a tendency to develop proteinopathy, which is the pathophysiological feature of neurodegenerative disorders such as Alzheimer disease (AD), chronic traumatic encephalopathy (CTE), and amyotrophic lateral sclerosis (ALS). This review mainly focuses on mechanisms related to AD, CTE, and ALS that are induced after TBI and their relevance to the advancement of these neurodegenerative diseases. This review encompasses acute effects and chronic neurodegenerative consequences after TBI for a better understanding of TBI-induced neuronal death and to design therapies that will effectively treat patients in the primary or secondary progressive stages.

Glial cells, besides participating as passive supporting matrix, are also proposed to be involved in the optimization of the interstitial space for synaptic transmission by tight control of ionic and water homeostasis. In adult mouse brain, inwardly rectifying K+ (Kir4.1) and aquaporin-4 (AQP4) channels localize to astroglial endfeets in contact with brain microvessels and glutamate synapses, optimizing clearance of extracellular K(+) and water from the synaptic layers. However, it is still unclear whether there is an age-dependent difference in the expressions of Kir4.1 and AQP4 channels specifically during postnatal development and aging when various marked changes occur in brain and if these changes region specific. RT-PCR and immunoblotting was conducted to compare the relative expression of Kir4.1 and AQP4 mRNA and protein in the early and mature postnatal (0-, 15-, 45-day), adult (20-week), and old age (70-week) mice cerebral and cerebellar cortices. Expressions of Kir4.1 and AQP4 mRNA and protein are very low at 0-day. A pronounced and continuous increase was observed by mature postnatal ages (15-, 45-days). However, in the 70-week-old mice, expressions are significantly up-regulated as compared to 20-week-old mice. Both genes follow the same age-related pattern in both cerebral and cerebellar cortices. The time course and expression pattern suggests that Kir4.1 and AQP4 channels may play an important role in brain K(+) and water homeostasis in early postnatal weeks after birth and during aging.

A study on the clinicoepidemiology of cerebral malaria (CM) and mild malaria (MM) among adults and children attending NSCB medical college hospital Jabalpur and civil hospital Maihar, Satna, in central India was undertaken. Of 1,633 patients, 401 were Plasmodium falciparum and 18 P. vivax. Of 401, 199 CM patients and 112 MM patients were enrolled. Severe complications among CM patients were jaundice (26%), acute renal failure (22%), respiratory distress (22%), severe malaria anemia (18%), hypotension (17%), hepatic encephalopathy (7.0%), and hematuria (5%). Among CM cases, seizures and severe malaria anemia were significantly higher in children (P < 0.0001) compared with adults, whereas jaundice (P < 0.0025), acute renal failure (P < 0.0001), and hematuria (P

Astroglia play multiple roles in brain function by providing matrix to neurons, secreting neurotrophic factors, maintaining K(+) and glutamate homeostasis and thereby controlling synaptic plasticity which undergoes alterations during aging. K(+) and glutamate homeostasis is maintained by astrocytes membrane bound inwardly rectifying K(+) channel (Kir4.1) and glutamate transporter-1 (GLT-1 or EAAT-2) proteins, respectively in the synapse and their expression may be altered due to traumatic brain injury (TBI). Also, it is not well understood whether this change is age dependent. To find out this, TBI was experimentally induced in adult and old male AKR strain mice using CHI technique, and expression of the Kir4.1 and GLT-1 in the pericontusional cortex at various time intervals was studied by Western blotting and semi quantitative RT-PCR techniques. Here, we report that expression of both Kir4.1 and GLT-1 genes at transcript and protein levels is significantly down regulated in the pericontusional ipsi-lateral cortex of old TBI mice as compared to that in the adult TBI mice as function of time after injury. Further, expression of both the genes starts decreasing early in old mice i.e., from the first hour after TBI as compared to that starts from fourth hour in adult TBI mice. Thus TBI affects expression of Kir4.1 and GLT-1 genes in age- and time dependent manner and it may lead to accumulations of more K(+) and glutamate early in the synapse of old mice as compared to adult. This may be implicated in the TBI induced early and severe neuronal depolarization and excito-neurotoxicity in old age.

We have investigated the frequencies and types of alpha-thal, beta-thal, and Hb variants among nearly 200 inhabitants of villages in the Mandla and Jabalpur districts of Madhya Pradesh in Central India. Over 85% were tribals of the Gond group. alpha-Thal, as -alpha 3.7/and -alpha 4.2/, and the nondeletional Koya Dora mutation were present at the combined frequency of 0.54. There were indications for the presence of other nondeletional types of alpha-thal. alpha-Globin gene triplications were not observed. Four of the six beta-thal alleles observed were in the tribal groups; two (G----C at codon 30 and G----A at IVS-I-1) were found for the first time. The simultaneous presence of an alpha-thal (-alpha/alpha alpha or -alpha/-alpha) greatly improved the clinical and hematological condition of the patients with Hb S-beta(+)-thal (IVS-I-5; G----C). The lower frequency of alpha-thal among the beta-thal heterozygotes (f = 0.32) may indicate that some of the beta-thal alleles in the tribal populations originated from an outside source. Forty-one subjects had SS; all but one had beta S with haplotype #31, while one chromosome had haplotype #17. The presence of an alpha-thal-2 (f = 0.53) in the SS patients did not affect hematological data. The Hb F levels varied between 7.5% and 42.5% with high G gamma values. No difference in Hb F level between males and females was observed. Lower Hb F levels were present in 10 SS patients with an alpha-thal-2 homozygosity (average 16% versus 23.5% for eight SS patients with alpha alpha/alpha alpha) suggesting a decreased formation of alpha gamma dimers in severe alpha chain deficiency. Several younger SS patients (less than 10 years) also had high Hb F levels (32-42%). Variations in the sequence at -530 of the beta-globin gene; i.e. in the so-called silencer sequence, were present in all beta S chromosomes with haplotype #31, but were not considered important for understanding the variability in the Hb F level. gamma-Globin gene deletions (gamma-thal) and triplications were not observed.

Differential microglial inflammatory responses play a role in regulation of differentiation and maturation of oligodendrocytes (OLs) in brain white matter. How microglia–OL crosstalk is altered by traumatic brain injury (TBI) and its impact on axonal myelination and neurological function impairment remain poorly understood. In this study, we investigated roles of a Na+/H+ exchanger (NHE1), an essential microglial pH regulatory protein, in microglial proinflammatory activation and OL survival and differentiation in a murine TBI model induced by controlled cortical impact. Similar TBI-induced contusion volumes were detected in the Cx3cr1-CreERT2 control (Ctrl) mice and selective microglial Nhe1 knockout (Cx3cr1-CreERT2;Nhe1flox/flox, Nhe1 cKO) mice. Compared to the Ctrl mice, the Nhe1 cKO mice displayed increased resistance to initial TBI-induced white matter damage and accelerated chronic phase of OL regeneration at 30 days post-TBI. The cKO brains presented increased anti-inflammatory phenotypes of microglia and infiltrated myeloid cells, with reduced proinflammatory transcriptome profiles. Moreover, the cKO mice exhibited accelerated post-TBI sensorimotor and cognitive functional recovery than the Ctrl mice. These phenotypic outcomes in cKO mice were recapitulated in C57BL6J wild-type TBI mice receiving treatment of a potent NHE1 inhibitor HOE642 for 1–7 days post-TBI. Taken together, these findings collectively demonstrated that blocking NHE1 protein stimulates restorative microglial activation in oligodendrogenesis and neuroprotection, which contributes to accelerated brain repair and neurological function recovery after TBI.