Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0085584 (encephalopathy)
 18,178 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stress can induce a serious epileptic encephalopathy that occurs during early infancy. Recent studies have revealed that prenatal stress exposure is a risk factor for the development of infantile spasms. Our previous work demonstrates that prenatal stress with betamethasone-induced alterations to the expression of the K+/Cl- co-transporter (KCC2) in gamma-aminobutyric acid (GABA) interneurons lowers the seizure threshold in exposed animals. Here, we further investigated the mechanisms involved in this KCC2 dysfunction and explored possible treatment options. We stressed Sprague-Dawley rats prenatally and further treated dams with betamethasone on gestational day 15, which increases seizure susceptibility and NMDA (N-Methyl-D-aspartate)-triggered spasms on postnatal day 15. In this animal model, first, we evaluated baseline calpain activity. Second, we examined the cleavage and dephosphorylation of KCC2. Finally, we checked the effect of a calpain inhibitor on seizure occurrence. The phosphorylated-N-methyl-Daspartate Receptor 2B (NR2B):non-phosphorylated NR2B ratio was found to be higher in the cortex of the prenatally stressed betamethasone model. We further found that the betamethasone model exhibited increased phosphorylation of calpain-2 and decreased phosphorylation of KCC2 and Glutamic acid decarboxylase 67 (GAD67). After using a calpain inhibitor in prenatal-stress rats, the seizure frequency decreased, while latency increased. GABAergic depolarization was further normalized in prenatal-stress rats treated with the calpain inhibitor. Our study suggests that calpain-dependent cleavage and dephosphorylation of KCC2 decreased the seizure threshold of rats under prenatal stress. Calpain-2 functions might, thus, be targeted in the future for the development of treatments for epileptic spasms.
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PMID:Calpain-2 as a Treatment Target in Prenatal Stress-induced Epileptic Spasms in Infant Rats. 3149 81

Repeated concussion represents a serious health problem as it can result in various brain pathologies, ranging from minor focal tissue injury to severe chronic traumatic encephalopathy. The calcium-dependent protease, calpain, participates in the development of neurodegeneration following concussion, but there is no information regarding the relative contribution of calpain-1 and calpain-2, the major calpain isoforms in the brain. We used a mouse model of repeated concussions, which reproduces most of the behavioral and neuropathological features of the human condition, to address this issue. Deletion of calpain-2 or treatment with a selective calpain-2 inhibitor for 2 weeks prevented most of these neuropathological features. Changes in TAR DNA binding protein 43 (TDP-43) subcellular localization similar to those found in human amyotrophic lateral sclerosis and frontotemporal dementia were also prevented by deletion of calpain-2 or treatment with calpain-2 inhibitor. Our results indicate that a selective calpain-2 inhibitor represents a therapeutic approach for concussion.
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PMID:Calpain-2 as a therapeutic target in repeated concussion-induced neuropathy and behavioral impairment. 3293 36