Excitotoxicity and neuroprotection

Abstract

Glutamate, the most widely used excitatory amino acid transmitter in the brain, stimulates ionotropic and metabotropic receptors. There is an increased release of glutamate after cerebral ischemia or hypoxia which could cause overstimulation of its receptors leading to an increase in the intracellular Ca 2+ concentration ([Ca 2+] i). Sustained elevation in [Ca 2+] i is assumed to set various pathological processes into motion which could degenerate neurons by activating proteases, lipases, endonucleases and nitric oxide synthases and by promoting the formation of free oxygen radicals. Drugs capable of inhibiting the increase in [Ca 2+] i such as calcium antagonists, NMDA and AMPA antagonists protect neurons against damage. To prevent Ca 2+ influx into neurons most efficaciously NMDA-operated and voltage-sensitive Ca 2+ channels were simultaneously blocked. Both the NMDA antagonist dizocilpine (MK-801) and the calcium antagonist nimodipine were added to glutamate-treated cultures of rat hippocampal neurons and these two drugs caused an overadditive neuroprotective effect. NMDA receptor stimulation leads to an augmented formation of NO and free oxygen radicals and that is the reason why radical scavengers are effective in protecting neurons against glutamate-induced damage. Furthermore, TGF-β1, the lesion form of the TGF-β family which is discussed to stabilize the cellular Ca 2+ homeostasis and to reduce free radical formation also protects neurons against excitotoxic damage. It is suggested that an increased [Ca 2+] i is significantly involved in neuronal damage and the inhibition of the increase in [Ca 2+] i protects neurons against damage.