Flunarizine 2HCl

Flunarizine is a selective calcium entry blocker.Flunarizine is a drug classified as a calcium channel blocker. Flunarizine is a non-selective calcium entry blocker with other actions including histamine H1 receptor blocking activity. It is effective in t

The ability of diphenylpiperazines to prevent neuronal death in dorsal root ganglion neurons in vitro after nerve growth factor deprivation and in vivo after axotomy.[Pubmed:8189223]

J Neurochem. 1994 Jun;62(6):2148-57.

The mechanism of neuroprotection by the calcium channel antagonist flunarizine against neuronal death is unknown. We investigated the ability of other calcium channel antagonists (cinnarizine, nimodipine, nicardipine, diltiazem, and verapamil), calmodulin antagonists, and calpain inhibitors to prevent neuronal death in rat dorsal root ganglion neurons in vitro after nerve growth factor (NGF) deprivation and the ability of cinnarizine and diltiazem to protect in vivo after axotomy. In vitro, only neurons treated with cinnarizine or flunarizine were protected from death after withdrawal. In vivo, cinnarizine, but not diltiazem, protected dorsal root ganglion neurons in rats after unilateral sciatic nerve crush. Intracellular calcium concentration ([Ca2+]i) was evaluated with fura 2 after NGF deprivation in vitro. Neurons "committed to die" 24 h after NGF deprivation displayed a decline in [Ca2+]i before visible morphological deterioration consistent with cell death. The influx of extracellular calcium was not necessary to produce neuronal death. Neurons deprived of NGF gradually lost the ability to respond to elevated external potassium with an increase in [Ca2+]i during the first 24 h after trophic factor deprivation. After 24 h, neurons deprived of NGF could not be rescued by readministration of NGF. Neurons protected from cell death with diphenylpiperazines maintained their response to high external potassium, suggesting continued membrane integrity. We speculate that diphenylpiperazines may protect sensory neurons via an unknown mechanism that stabilizes cell membranes.

Ca++ and Na+ channels involved in neuronal cell death. Protection by flunarizine.[Pubmed:1850815]

Life Sci. 1991;48(20):1881-93.

Flunarizine, a class IV Ca++ antagonist non-selective for slow Ca++ channels, has been shown to be beneficial in the prophylactic treatment of migraine, the treatment of vertigo, and as add-on treatment in therapy-resistant forms of epilepsy. Flunarizine protects the brain against functional and/or structural neuronal damage in various animal models of cerebral ischemia. In addition to its cerebrovascular effect, flunarizine has also direct neuroprotective actions. New data have emerged on flunarizine with regard to Ca++ and Na+ channels in neuronal cells. There are several possible mechanisms involved in the mode of action of flunarizine. Flunarizine may block Ca++ and Na+ channels, both of which may flux Ca++ as well as Na+. A decrease in Ca++ influx may prevent further release of glutamate, and activation of NMDA receptor gated Ca++ channels at physiological pH. A decrease in Na+ influx may prevent cytotoxicity secondary to a large gain in intracellular Ca++, by reverse operation of the Na+/Ca++ exchanger. This mechanism may be important when the glycolytic rate is increased with concomitant acidosis, and phospholipids are broken down as occurs typically during ischemia. Given the complexity of biochemical events leading to cell death, blocking exclusively one channel subtype is not likely to yield sufficient protection. Hence, it may be useful to develop anti-ischemic compounds which act on a series of pathways involved in Ca++ overload, rather than selectively block one such channel.