Potential role of neurotensin in glutamate-induced neurotoxicity: Possible mechanisms and implications for neurodegenerative disorders.

The tridecapeptide neurotensin has been demonstrated to increase glutamate levels in discrete rat brain regions, leading to the hypothesis of a possible involvement of the peptide in neurodegenerative pathologies. The present article reviews morphological and biochemical findings about the role of neurotensin in modulating glutamate excitotoxicity in primary cultures of rat cortical neurons and rat mesencephalic dopaminergic neurons. Since the enhancement of glutamate signal is responsible, at least in part, for the neurodegeneration of the dopaminergic neurons and cortical neurons occurring during chronic neurodegenerative disorders, the observed neurotensin-induced-increase of glutamate levels in the basal ganglia and cerebral cortex in pathological conditions should result in an amplification of the excitotoxic effects of glutamate. The possible existence of a reciprocal interaction between neurotensin and NMDA receptor mediated signals, through the activation of protein kinase C favouring the depolarization and the entry of calcium, strengthens the idea that neurotensin is involved in the amplification of glutamate-induced neurotoxicity, since the NMDA receptors are especially important for the toxic actions of glutamate. The antagonistic effect exerted by SR48692 on the neurotensin-amplificated glutamate excitotoxicity could suggest the use of selective neurotensin receptor antagonists in combination with conventional drug treatments as a novel therapeutic approach for the treatment of neurodegenerative pathologies