Zao C. Xu is a Professor in Indiana University School of Medicine, USA. He has more than 30 years of experience in Neuroscience research using electrophysiological, morphological and molecular biological approaches. The major research projects in his laboratory are the mechanisms underlying the neuronal injury/survival after cerebral ischemia and traumatic brain injury and the mechanisms of seizure/epilepsy following acute neurological disorders such as stroke and traumatic brain injury.
Seizures are the most common neurological sequelae following brain injury such as stroke and traumatic brain injury (TBI). The mechanisms of seizure/epilepsy in these acute neurological disorders remain unclear. Recent studies indicated that epilepsy could be mediated by energy metabolism related proteins such as Sestrin3 (SESN3). The present study attempted to reveal the contribution of SESN3 to seizure generation in cerebral ischemia in diabetic condition and TBI. Transient global ischemia was produced in adult rats and mice. Diabetes was induced by i.p. injection of 50 mg/kg streptozotocin (STZ). TBI was induced in mice using the control cortical impact method. The seizure activity was defined by the Racine scale III-V. The neuronal death in the brain was determined by hematoxy lineosin staining. The expression levels of SESN3 were analyzed by western blotting and immunohistochemistry. The neuronal excitability was recorded using electrophysiological approaches. The blood glucose levels was >300 mg/ dL in animals one week after STZ injection. Th e seizure rate was significantly increased after 15 min ischemia. No obvious neuronal damage was observed in hippocampus and cerebral cortex. SESN3 expression in hippocampus was signifi cantly increased in diabetic animals with post-ischemia seizures. The potassium channel expression and currents in hippocampal neurons were decreased and neuronal excitability increased in these animals. The seizure rate was signifi cantly decreased from 60% of wild type mice to 15% of SESN3 knockout mice after 15 min ischemia. In mice with TBI, the seizure was induced by GABAA receptor blocker Pentyleneletrazole (PTZ, 40 mg/Kg, i.p.). One week after TBI, the latency of seizure onset was reduced in SESN3 KO mice; the input resistance of hippocampal neurons decreased and the rheobase increased in these KO animals. These data suggest that SESN3 involved in seizure generation aft er brain injury by affecting neuronal excitability.
Lingling Zhu has completed her PhD at Jichi Medical University, Japan and Postdoctoral studies from Academy of Military Medical Sciences, Beijing, China. She is the Director of Department of Cognitive Sciences of the Institute of Military Cognition and Brain Science. As the first author or corresponding author, she has published more than 25 papers in reputed journals and was invited to write English chapters.
FG-4592, an inhibitor of prolyl hydroxylase (PHD), stabilizes HIF-1α and has been used in Phase III trials for the treatment of anemia patients with chronic kidney disease (CKD). Chronic Unpredictable Mild Stress (CUMS), an animal model recapitulating the core symptoms of human depression, showed an atrophy of dendritic spines and a decrease in neurogenesis on hippocampus. In the current study, we investigated whether FG-4592 exhibits anti-depressant effect in rat CUMS model and its possible molecular mechanisms. We found that FG-4592 not only reversed the depressive behaviors, but also reversed impaired learning and spatial memory in the rat CUMS model. Moreover, FG-4592 increased hippocampal neurogenesis and synaptic plasticity including the density and the length of dendritic spines. At the molecular level, FG-4592 increased HIF-1α expression and activation, hence increase its target genes expression of EPO and BDNF (and other HIF target genes). Taken together, our findings demonstrated that FG-4592 has a therapeutic potential similar to an antidepressant in animal models of depression and could be developed as a treatment therapeutic option against this pathophysiological state.