ns-7 and Infarction--Middle-Cerebral-Artery

A novel series of pyrrolidine derivatives as Na(+) channel blockers was synthesized and evaluated for their inhibitory effects on neuronal Na(+) channels. Structure-activity relationship (SAR) studies of a pyrrolidine analogue 2 led to the discovery of 5e as a potent Na(+) channel blocker with a low inhibitory action against human ether-a-go-go-related gene (hERG) channels. Compound 5e showed remarkably neuroprotective activity in a rat transient middle cerebral artery occlusion (MCAO) model, suggesting that 5e would act as a neuroprotectant for ischemic stroke.

Topics: Animals; Disease Models, Animal; Ether-A-Go-Go Potassium Channels; Humans; Infarction, Middle Cerebral Artery; Neurons; Neuroprotective Agents; Pyrrolidines; Rats; Sodium Channel Blockers; Stroke; Structure-Activity Relationship

NS-7 is a novel, voltage-dependent Na(+) and Ca(2+) channel blocker. This study evaluated the in vivo neuroprotective effect of NS-7 in a rat transient focal ischemic model when administered during occlusion. Left middle cerebral artery occlusion was induced in adult male Sprague-Dawley rats for 120 min using an intraluminal thread method. The rats received a single intravenous injection of NS-7 or saline (control group) just after the onset of ischemia, and at 30, 60 and 120 min after ischemia. Their brains were removed after 48 h reperfusion, sectioned, and stained with hematoxylin and eosin. Animals were evaluated by neurological examination at 120 min ischemia and 48 h reperfusion. Infarcted cortex and striatum were measured quantitatively and infarction volumes were calculated. Cortical infarction volumes were 128+/-74 (NS-7) and 214+/-64 mm(3) (control) immediately after the ischemia group, 155+/-48 (NS-7) and 225+/-12 mm(3) (control) after the 30 min group, 160+/-54 (NS-7) and 225+/-48 mm(3) (control) after the 60 min group, and 176+/-43 (NS-7) and 223+/-38 mm(3) (control) after the 120 min group. Cortices in NS-7-treated groups were significantly less infarcted than in control groups at all treatment times. There was no significant difference in the striatal infarction volume between the treatment and control groups. Neurological examination showed that hemiparesis and abnormal posture of the NS-7 groups were significantly more improved at 48 h reperfusion than those of the control groups without posture examination in the 120 min group. These observations suggest that NS-7 may be a new potential therapeutic agent for the acute phase of cerebral infarction.

Topics: Animals; Brain; Calcium Channel Blockers; Infarction, Middle Cerebral Artery; Male; Models, Animal; Neuroprotective Agents; Pyrimidines; Rats; Rats, Sprague-Dawley; Sodium Channel Blockers; Time Factors

The effect of a novel Na+/Ca2+ channel blocker NS-7 [4-(4-fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy) pyrimidine hydrochloride] on the cerebral infarction, edema, and mortality was examined in rats with a transient middle cerebral artery occlusion (MCAO), and the effective plasma concentration of this compound for producing the cerebroprotective action was subsequently determined. MCA was occluded by inserting a thread through internal carotid artery for 2 h, and then recirculated for 6 h. NS-7 (0.125-1 mg/kg), when injected i.v. immediately after recirculation, significantly reduced the infarct volume as well as the cerebral edema. Delayed treatment with NS-7 at 1 h after recirculation produced an equivalent inhibition of the infarction, and was still effective, although to a lesser extent, when injected at 2 h but not 3 h after recirculation. Glycerol (4 g/kg) suppressed the cerebral edema but did not reduce the size of cerebral infarction in the cerebral cortex or striatum. Therefore, it is likely that the suppression of brain edema does not always lead to the reduction of the infarct size. NS-7 treated in combination with glycerol further decreased the water content in the occluded brain. Moreover, NS-7 significantly lowered the mortality observed up to 10 days after a transient MCAO. From these data, it is suggested that the presence of NS-7 in plasma during 1 to 3 h after recirculation is important for producing the neuroprotective action. To determine the pharmacologically effective plasma concentration of NS-7, the effect of continuous infusion of this compound on the cerebral infarction was examined. Infusion of NS-7 at 0.3 mg/kg over 2 h, starting immediately after recirculation, significantly reduced the infarct size. Its plasma concentration during 1 to 3 h was 14.5 to 28.5 ng/ml (36.9-72.3 nM). From these finding it is suggested that NS-7 has a potent anti-infarct action in addition to antiedema action in the rat transient MCAO model. Moreover, its effective plasma concentration was assumed to be 36.9 to 72.3 nM.

Topics: Animals; Brain Chemistry; Brain Edema; Calcium Channel Blockers; Carotid Artery, Internal; Electrophysiology; Glycerol; Infarction, Middle Cerebral Artery; Ischemic Attack, Transient; Ligation; Male; Middle Cerebral Artery; Neuroprotective Agents; Pyrimidines; Rats; Rats, Sprague-Dawley; Sodium Channel Blockers

The effect of a novel Na+/Ca2+ channel blocker NS-7 [4-(4-fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy)pyrimidine hydrochloride] on the cerebral infarction, edema and brain energy metabolism was investigated in rats after permanent middle cerebral artery occlusion (MCAO). The infarction and brain water content were evaluated at 48 h and 24 h after MCAO, respectively. A single bolus injection of NS-7 (0.03125-0.25 mg/kg) immediately after MCAO produced a dose-dependent reduction in the infarct volume as well as edema both in the cerebral cortex and striatum. Glycerol (4 g/kg) also decreased water content both in the occluded and non-occluded brain, but it did not reduce the size of cerebral infarction. Unlike glycerol, NS-7 did not change the water content in non-occluded brain. Moreover, a significant protective action was still observed even when NS-7 was injected once at 12 h after occlusion. In addition, NS-7 significantly reversed the decrease in tissue ATP content observed at 3 h but not at 0.5 h after MCAO. These findings suggest that a Na+/Ca2+ channel blocker NS-7 protects cerebral tissues against ischemic insults by improving the disturbance of cerebral energy metabolism and suppressing the cerebral edema.

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Animals; Brain; Brain Edema; Calcium Channel Blockers; Cerebral Infarction; Cryoprotective Agents; Glycerol; Infarction, Middle Cerebral Artery; Male; Neuroprotective Agents; Pyrimidines; Rats; Rats, Sprague-Dawley; Sodium Channel Blockers

We have previously shown that NS-7 [4-(4-fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy)pyrimidine hydrochloride] reduces the size of cerebral infarction measured by 2,3,5-triphenyltetrazolium chloride staining at 48 h after permanent middle cerebral artery occlusion (MCAO) in rats. To determine whether NS-7 improves the pathological and behavioral changes at the chronic stage of MCAO, the effect of this compound on the cerebral infarction as well as the neurological and cognitive impairments was investigated 7 days after MCAO. Single or five daily injections of NS-7 (0.125-0.5 mg/kg, i.v.) significantly reduced the infarct volume and improved the neuronal dysfunction including the hind leg paralysis, walking disability and motor incoordination, and the deficit of passive avoidance task, although the neuroprotective efficacy was not different among these dosing regimens. On the other hand, the effects of single versus repeated injections of NS-7 at 0.1 or 0.2 mg/kg on the neurological symptoms were compared at 4 weeks after MCAO. At a lower dose, repeated but not single injection of NS-7 significantly improved the neurological symptoms, although the single injection was effective at a higher dose. From these findings, it is suggested that NS-7 reverses the behavioral and cognitive dysfunction observed at the chronic stage of cerebral ischemia by suppressing the cerebral infarction.

Topics: Animals; Avoidance Learning; Behavior, Animal; Calcium Channel Blockers; Cerebral Infarction; Chronic Disease; Cognition Disorders; Dose-Response Relationship, Drug; Infarction, Middle Cerebral Artery; Male; Neuroprotective Agents; Pyrimidines; Rats; Rats, Sprague-Dawley; Recovery of Function; Sodium Channel Blockers