Reduced expression of I_A channels is associated with postischemic seizures in hyperglycemic rats

Abstract

Poststroke seizures are considered to be the major cause of epilepsy in the elderly. The mechanisms of poststroke seizures remain unclear. A history of diabetes mellitus has been identified as an independent predictor of acute poststroke seizures in stroke patients. The present study sought to reveal the mechanisms for the development of postischemic seizures under hyperglycemic conditions. Transient forebrain ischemia was produced in adult Wistar rats by using the four-vessel occlusion method. At the normal blood glucose level, seizures occurred in ∼50% of rats after 25 min of ischemia. However, in rats with hyperglycemia, the incidence rate of postischemic seizures was significantly increased to 100%. The occurrence of postischemic seizures was not correlated with the severity of brain damage in hyperglycemic rats. Mannitol, an osmotic diuretic agent, could neither prevent postischemic seizures nor alleviate the exacerbated brain damage in the presence of hyperglycemia. K(+) channels play a critical role in controlling neuronal excitability. The expression of A-type K(+) channel subunit Kv4.2 in the hippocampus and the cortex was significantly reduced in hyperglycemic rats with seizures compared with those without seizures. These results suggest that the reduction of Kv4.2 expression could contribute to the development of postischemic seizures in hyperglycemia.

MicroRNA-Mediated Downregulation of the Potassium Channel Kv4.2 Contributes to Seizure Onset

“…Reduced expression and impaired function of Kv4.2 were observed in at least three different rodent models of acquired epilepsy (pilocarpine-induced temporal lobe epilepsy, traumatic brain injury and ischemic insult) (Monaghan et al, 2008, Lei et al, 2012, Lei et al, 2014, Bernard et al, 2004) and in rats acutely following evoked seizure (Francis et al, 1997, Tsaur et al, 1992). Reduction of Kv4.2 expression may thus be a pathological mechanism contributing to seizures and epilepsy; however, the molecular mechanisms regulating Kv4.2 expression during neuronal hyperactivity are unknown, and it is not clear if downregulation of Kv4.2 expression contributes to seizure onset.…”

Reduced expression of IA channels is associated with post-ischemic seizures

“…Thus, it seems that seizures are the cause of aggravated brain damage. Our recent published results excluded the causal relationship of neuronal damage with the seizure development after hyperglycemic ischemia (Lei et al, 2014). Furthermore, based on the result that seizures could occur in rats without obvious brain damage in the cortex and hippocampus (Fig.…”

“…The specific mechanisms by which hyperglycemia increase post-stroke seizures is not known, although several have been proposed based on experimental results from rats with pre-ischemic hyperglycemia. The proposed mechanisms include more tissue acidosis (Li et al, 1995), selective damage to GABAergic neurons in the substantia nigra pars reticulata (SNPR) (Smith et al, 1988) greater brain edema (Morimoto et al, 1996; Warner et al, 1987), reduction of potassium channels (Lei et al, 2014), and activation of Toll-like receptor 4 (TLR-4) pathway (Liang et al, 2014). …”

“…In neurons, Kv4 subunits, together with, KChIPs and DPPX, give rise to the majority of somatodendritic I A currents (An et al, 2000; Nadal et al, 2003; Sheng et al, 1992). In our previous studies, we found that the reduction of I A currents and channels contributes to the seizure development after hyperglycemic ischemia (Lei et al, 2014). However, the involvement of I A currents and channels in the post-ischemic seizures in rats with normal glucose levels has not been elucidated.…”