Contribution of Downregulation of L-type Calcium Currents to Delayed Neuronal Death in Rat Hippocampus after Global Cerebral Ischemia and Reperfusion

Abstract

Transient forebrain ischemia induces delayed, selective neuronal death in the CA1 region of the hippocampus. The underlying molecular mechanisms are as yet unclear, but it is known that activation of L-type Ca 2ϩ channels specifically increases the expression of a group of genes required for neuronal survival. Accordingly, we examined temporal changes in L-type calcium-channel activity in CA1 and CA3 pyramidal neurons of rat hippocampus after transient forebrain ischemia by patch-clamp techniques. In vulnerable CA1 neurons, L-type Ca 2ϩ -channel activity was persistently downregulated after ischemic insult, whereas in invulnerable CA3 neurons, no change occurred. Downregulation of L-type calcium channels was partially caused by oxidation modulation in postischemic channels. Furthermore, L-type but neither N-type nor P/Q-type Ca 2ϩ -channel antagonists alone significantly inhibited the survival of cultured hippocampal neurons. In contrast, specific L-type calcium-channel agonist remarkably reduced neuronal cell death and restored the inhibited channels induced by nitric oxide donor. More importantly, L-type calcium-channel agonist applied after reoxygenation or reperfusion significantly decreased neuronal injury in in vitro oxygen-glucose deprivation ischemic model and in animals subjected to forebrain ischemia-reperfusion. Together, the present results suggest that ischemia-induced inhibition of L-type calcium currents may give rise to delayed death of neurons in the CA1 region, possibly via oxidation mechanisms. Our findings may lead to a new perspective on neuronal death after ischemic insult and suggest that a novel therapeutic approach, activation of L-type calcium channels, could be tested at late stages of reperfusion for stroke treatment.

Glucopsychosine increases cytosolic calcium to induce calpain-mediated apoptosis of acute myeloid leukemia cells

“…This observed pattern of reduced surface calcium channel expression is similar to other disease states such as atrial fibrillation [72], colonic inflammation [73] and cerebral ischemia [74]. Although the physiological consequence of this under-expression in AML cells is not known, reduced calcium channel expression was associated with delayed neuronal death following tissue hypoxia [74]. It is therefore possible that AML cells under-express extracellular calcium channels to increase survival, as this would prevent increases in cytosolic calcium that would otherwise result in activation of apoptotic cell death.…”

“…First, interrogation of publically available AML gene expression databases indicated that surface receptors regulating cytosolic calcium levels are significantly under-expressed in AML cells compared to normal cells. This observed pattern of reduced surface calcium channel expression is similar to other disease states such as atrial fibrillation [72], colonic inflammation [73] and cerebral ischemia [74]. Although the physiological consequence of this under-expression in AML cells is not known, reduced calcium channel expression was associated with delayed neuronal death following tissue hypoxia [74].…”

Dysregulation of intracellular calcium homeostasis is responsible for neuronal death in an experimental model of selective hippocampal degeneration induced by trimethyltin

“…Although this influx of Ca 2+ represents only a transient and small fraction of the total that accumulates in the cytoplasm during TMT exposure, it could nonetheless be involved in activating intracellular pathways leading to the TMT-induced cell death observed in both in vitro and in vivo systems. In fact, Ca 2+ signalling through voltage-gated Ca 2+ channels, including the L-type has been shown to play a crucial role in regulating cell fate (Nicotera and Orrenius 1998;Tao et al 1998;Berridge et al 2000;Dolmetsch et al 2001;West et al 2001;Toescu et al 2004;Webster et al 2006;Li et al 2007). Cultured rat cortical neurons have been shown to be more resistant than cultured rat hippocampal neurons to TMTinduced apoptosis (Thompson et al 1996).…”

Differential gene expression profiling of large and small retinal ganglion cells

“…Provided that oxidative stress is very common in many retinal degenerations, the constitutively increased activity of MAPK-ERK -EGR1 network may represent potential mechanism of increased vulnerability of LRGCs to stress. In parallel to this mechanism, relatively decreased activity of calcium transport system in LRGC can selectively affect survival of this sub-population during calcium overload typically observed in stress (Nakamura et al 1999;Li et al 2007). Although we detected relatively subtle differences in transcriptome activity between the two subgroups of RGCs, it is conceivable that greater differences and contrast responses will be revealed upon exposure of the retina to stress.…”