title: Neuroprotective effects of selective N-type VGCC blockade on stretch-injury-induced calcium dynamics in cortical neurons.
abstract: Acute elevation in intracellular calcium ([Ca(2+)](i)) following traumatic brain injury (TBI) can trigger cellular mechanisms leading to neuronal dysfunction and death. The mechanisms underlying these processes are not completely understood, but calcium influx through N-type voltage-gated calcium channels (VGCCs) appears to play a central role. The present study examined the time course of [Ca(2+)](i) flux, glutamate release, and loss of cell viability following injury using an in vitro neuronal-glial cortical cell-culture model of TBI. The effects of N-channel blockade with SNX-185 (e.g. omega-conotoxin TVIA) before or after injury were also examined. Neuronal injury produced a transient elevation in [Ca(2+)](i), increased glutamate release, and resulted in neuronal and glial death. SNX-185 administered before or immediately after cell injury reduced glutamate release and increased the survival of neurons and astrocytes, whereas delayed treatment did not improve cell survival but significantly facilitated the return of [Ca(2+)](i) to baseline levels. The new findings that N-type VGCCs are critically involved in injury-induced glutamate release and recovery of [Ca(2+)](i) argue for continued investigation of this treatment strategy for the clinical management of TBI. In particular, SNX-185 may represent an effective class of drugs that can significantly protect injured neurons from the secondary insults that commonly occur after TBI.
authors.affiliation: Department of Neurological Surgery, School of Medicine, University of California, Davis, Sacramento, California 95817, USA. krshahlaie@gmail.com
authors.forename: Kiarash
authors.initials: K
authors.lastname: Shahlaie
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Lyeth
authors.forename: Gene G
authors.initials: GG
authors.lastname: Gurkoff
authors.forename: J Paul
authors.initials: JP
authors.lastname: Muizelaar
authors.forename: Robert F
authors.initials: RF
authors.lastname: Berman
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001930:Brain Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D020864:Calcium Channels, N-Type / Q000187:drug effects* / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects* / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018920:Coculture Techniques; D018698:Glutamic Acid / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D013997:Time Factors; D020960:omega-Conotoxins / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; D020960:omega-Conotoxins; C087968:omega-conotoxin TVIA; D018698:Glutamic Acid; D002118:Calcium