Open AccessA Review of the Neuroprotective Properties of the 5‐HT 1A Receptor Agonist Repinotan HC1 (BAY × 3702) in Ischemic Stroke
Author(s) -
Berends A. C.,
Luiten P. G. M.,
Nyakas C.
Publication year - 2005
Publication title -
cns drug reviews
Language(s) - English
Resource type - Journals
eISSN - 1527-3458
pISSN - 1080-563X
DOI - 10.1111/j.1527-3458.2005.tb00055.x
Subject(s) - neuroprotection , agonist , glutamate receptor , pharmacology , neuroscience , hyperpolarization (physics) , 5 ht1a receptor , medicine , receptor , biology , chemistry , 5 ht receptor , serotonin , organic chemistry , nuclear magnetic resonance spectroscopy
Repinotan HC1 (repinotan, BAY × 3702), a highly selective 5‐HT 1A receptor agonist with a good record of safety was found to have pronounced neuroprotective effects in experimental models that mimic various aspects of brain injury. Repinotan caused strong, dose‐dependent infarct reductions in permanent middle cerebral artery occlusion, transient middle cerebral artery occlusion, and traumatic brain injury paradigms. The specific 5‐HT 1A receptor antagonist WAY 100635 blocked these effects, indicating that the neuroprotective properties of repinotan are mediated through the 5‐HT 1A receptor. The proposed neuroprotective mechanisms of repinotan are thought to be the result of neuronal hyperpolarization via the activation of G protein‐coupled inwardly rectifying K + channels upon binding to both pre‐ and post‐synaptic 5‐HT 1A receptors. Hyperpolarization results in inhibition of neuron firing and reduction of glutamate release. These mechanisms, leading to protection of neurons against overexcitation, could explain the neuroprotective efficacy of repinotan per se, but not necessarily the efficacy by delayed administration. The therapeutic time window of repinotan appeared to be at least 5 h in in vivo animal models, but may be even longer at higher doses of the drug. Experimental studies indicate that repinotan affects various mechanisms involved in the pathogenesis of brain injury. In addition to the direct effect of repinotan on neuronal hyperpolarization and suppression of glutamate release this compound affects the death‐inhibiting protein Bcl‐2, serotonergic glial growth factor S‐100β and Nerve Growth Factor. It also suppresses the activity of caspase‐3 through MAPK and PKC α ; this effect may contribute to its neuroprotective efficacy. The dose‐ and time‐dependent neuroprotective efficacy of repinotan indicates that the drug is a promising candidate for prevention of secondary brain damage in brain‐injured patients suffering from acute ischemic stroke. Unfortunately, however, the first, randomized, double blind, placebo‐controlled clinical trial did not demonstrate the efficacy of repinotan in acute ischemic stroke.