CGS‐19755, A competitive NMDA receptor antagonist, reduces calcium‐calmodulin binding and improves outcome after global cerebral ischemia

Abstract

We evaluated several doses of cis-4-(phosphonomethyl)-2-piperidine-carboxylic acid (CGS-19755), a potent competitive N-methyl-D-aspartate (NMDA) receptor antagonist, systemically administered either before or after 20 to 30 minutes of global ischemia in rats. We measured outcome by mortality, histological damage by light microscopy, and learning ability on an eight-arm maze, and determined the drug's mechanism of action by an immunohistochemical assay of calcium-calmodulin binding. High-dose treatment begun prior to ischemia resulted in reduced cellular damage in severely ischemic hippocampal tissue, but also caused high mortality due to respiratory depression. Treatment begun 30 minutes after ischemia resulted in little histological protection but significantly improved learning ability when tested 1 month after ischemia, and did not increase mortality. Furthermore, CGS-19755, 10 mg/kg intraperitoneally, begun either before or after ischemia substantially reduced calcium influx into ischemic neurons as evidenced by reduced calcium-calmodulin binding. We conclude that CGS-19755 prevents calcium entry into ischemic neurons and may be effective therapy for very acute cerebral ischemia.

Temporal relation of calcium-calmodulin binding and neuronal damage after global ischemia in rats.

“…22 In Our studies demonstrate that with increasing durations of ischemia, there is a corresponding increase of Ca 2+ influx and Ca-CaM binding. The concept that the degree of Ca 2+ influx is directly linked to the duration of ischemia is important in postulating Ca 2+ as a mediator of neuronal injury.…”

“…22 Brain sections of groups of six rats exposed to 5,10, or 20 minutes of ischemia after 2 hours, 24 hours, or 7 days of reperfusion were incubated in sheepinduced CaM antibody, which binds specifically to free CaM (i.e., the CaM not bound to Ca 2+ and target protein). The sections were incubated with rabbit antisheep peroxidase-conjugated secondary antibody, which binds to and stains only CaM-antibody complex.…”

Clinical trials for cytoprotection in stroke

“…28 Forty-six patients with ischemic carotid artery territory stroke [National Institute of Health Stroke Scale (NIHSS) score [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] were enrolled within 24 h of symptom onset. In part A, patients were randomized 3:1 to a single bolus of Cerestat or placebo.…”

Ion Channels as Drug Targets in Central Nervous System Disorders

“…(37) in preclinical animal tests produced anticonvulsant, anxiolytic and anti-ischemic effects [213]. The compound reduced neuronal damage in animal models of stroke [214][215][216]. In the rat model of global cerebral ischemia selfotel treatment (dose ranged from 10 to 30 mg/kg intraperitoneally) resulted in neuroprotection that was observed when administration was not delayed more than 30 minutes after the onset of ischemia [215].…”

“…The compound was also effective in a rabbit model of reversible CNS ischemia [216]. Grotta et al [215] evaluated the safety and tolerability of selfotel in patients with acute ischemic stroke. The study showed that although adverse effects are related with the treatment in a dosedependent fashion, a single intravenous dose of 1.5 mg/kg is safe and tolerable with adverse experiences that are controllable.…”