Differential pattern of expression of voltage-gated sodium channel genes following ischemic brain injury in rats

Abstract

This study investigated the effects of brain ischemia on sodium channel gene (NaCh) expression in rats. Using quantitative RT-PCR, our findings demonstrated the expression ratio of NaCh genes in normal rat brain to be Na(v)1.1 > Na(v)1.8 > Na(v)1.3 > Na(v)1.7 (rBI > PN3 > rBIII > PN1). In contrast, brain injury caused by middle cerebral artery occlusion (MCAo) for 2 h followed by reperfusion significantly down-regulated Na(v)1.3 and Na(v)1.7 genes in both injured and contralateral hemispheres; whereas the Na(v)1.8 gene was down regulated in only the injured hemisphere (though only acutely at 2 or 2-6 h post-MCAo). However, the time-course of NaCh gene expression revealed a significant down-regulation of Na(v)1.1 only in the ischemic hemisphere beginning 6 h post-MCAo and measured out to 48 h post-MCAo. In a separate preliminary study Na(v)1.2 (rBII) gene was found to be expressed at levels greater than that of Na(v)1.1 in normal rats and was significantly down regulated at 24 h post-MCAo). Our findings document, for the first time, quantitative and relative changes in the expression of various NaCh genes following ischemic brain injury and suggest that the Na(v)1.1 sodium channel gene may play a key role in ischemic injury/recovery.

Neuronal Sodium Channels in Neurodegeneration and Neuroprotection

“…1, while other NaCh genes were not significantly affected by direct activation of these voltage-gated sodium channels. These data are consistent with our recent in vivo findings in which temporary middle cerebral artery occlusion (MCAo) produced a time-dependent down-regulation of Nav1.1 gene in the injured hemisphere (Yao et al, 2002). Furthermore, the present study is 1) the first to demonstrate a selective reversal of veratridine-mediated down-regulation of Navl.1 gene expression and 2) documents a direct correlation of RS-100642 neuroprotection and reversal of sodium channel gene expression.…”

“…Although these results differ slightly from those reported earlier from our laboratory in adult rat brain (Yao et al, 2002) where the abundance of Navl.2 channel mRNA is also greatest, but followed by Navl.1, Nal.8, Nal.3 and Na'1.7 mRNA. It should be noted that in both cases Navl.2 gene expression is the most abundant, whereas the Na1l.7 transcript is the least abundant.…”

“…The time-course of changes in Nal. 1 gene expression in earlier in vivo studies revealed a significant down-regulation in the injured brain hemisphere from 6 h to 48 h post-MCAo, with a maximal decrease being observed at 24 h post-injury (Yao et al, 2002). In the present study we selected the same optimal time-interval to demonstrate the effects of voltage-gated sodium channel activation on regulation of these five NaCh genes in primary neuronal cultures.…”

“…Our findings indicated that Na,1. 1 and Na,1.2 NaCh genes were significantly down-regulated at 24 hr post-injury (Yao et al, 2002). The present studies were undertaken to determine the changes in expression of these five neuronal sodium channel …”

Down-regulation of the sodium channel Nav1.1 α-subunit following focal ischemic brain injury in rats: In situ hybridization and immunohistochemical analysis

“…This phenomenon may represent an endogenous response to limit energy utilization due to the excitotoxic state of the ischemic brain but may also participate in the electrophysiological disturbances inherent to ischemic brain injury. Previous studies have demonstrated the down-regulation the NaCh subunits Na v 1.1, Na v 1.2, Na v 1.3, Na v 1.7, Na v 1.8 following focal ischemic brain injury in the rat (Yao et al, 2002). In particular, mRNA levels of Na v 1.1 exhibited the most dramatic and sustained drop with greater than 75% reductions at 48 h post-MCAo as compared to normal levels (Yao et al, 2002).…”