Neuroprotective Effects of Selective N-Type VGCC Blockade on Stretch-Injury-Induced Calcium Dynamics in Cortical Neurons

Abstract

Acute elevation in intracellular calcium ([Ca 2þ ] 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 2þ ] 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. o-conotoxin TVIA) before or after injury were also examined. Neuronal injury produced a transient elevation in [Ca 2þ ] 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 2þ ] i to baseline levels. The new findings that N-type VGCCs are critically involved in injury-induced glutamate release and recovery of [Ca 2þ ] 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.

Neuroadhesive L1 coating attenuates acute microglial attachment to neural electrodes as revealed by live two-photon microscopy

“…Chemokines such ATP, UDP, and glutamate are known to incite directed microglial process extension along the chemokine gradient [113–117] . Upon mechanical trauma, astrocytes and neurons release ATP and glutamate into the extracellular space, serving as chemokines for surrounding microglia [118–120]. This effect is conserved across many paradigms of mechanical trauma, including deep-brain stimulator implantation in humans [121].…”

Interneuronal calcium channel abnormalities in posttraumatic epileptogenic neocortex

“…For example, calcium channel loss in excitatory versus inhibitory terminals is likely to induce contrasting effects on circuit excitability. Also, blockade of N-channels can prevent injury-induced glutamate release in a model of traumatic brain injury (Shahlaie et al, 2010). In contrast, N-channel loss in injured presynaptic inhibitory terminals might contribute to decreased release probability of GABA and increased failure rate for eIPSCs in UCs (Faria and Prince 2010; Ma and Prince 2009).…”

Dopamine and full‐field illumination activate D1 and D2‐D5‐type receptors in adult rat retinal ganglion cells

“…Changes in intracellular free Ca 2+ concentration were detected by ratio-imaging fura-2 fluorescence intensity, following a protocol modified from that of Shahlaie et al (2010). Prior to each imaging session, adult rat retinae were dissociated, cells were immunopanned as in the patch-clamp measurements described here, and fura-2 AM was dissolved in dimethyl sulfoxide and diluted to a final concentration of 5 μM in Neurobasal-A culture medium (supplemented with 2% B-27).…”