Title

 

Authors

L. Ferraro, T. Antonelli, M.C. Tomasini, S. Beggiato and S. Tanganelli
 
Department of Clinical and Experimental Medicine, University of Ferrara, Ferrara (Italy).

 

Abstract

Neurotensin (NT) is a brain-gut biologically active tridecapeptide originally isolated from bovine hypothalamus. It is widely distributed in central and peripheral nervous systems of mammals, including humans, where it behaves as a neurotransmitter or neuromodulator. The numerous physiological functions modulated by the peptide are mainly mediated through the interaction with three specific receptor subtypes, referred to NTS₁, NTS₂ and NTS₃. In the central nervous system, one of the better known actions of NT is to regulate the functional activity of the basal ganglia, mainly through NTS₁ receptors, largely distributed in this brain area. Several studies have undoubtedly demonstrated the existence, in the basal ganglia, of a functional interaction between NT and dopamine [1, 2]. More recently, it has been provided evidence that NTS₁ receptor activation promotes and reinforces endogenous glutamate signalling in discrete brain regions. The increase of striatal, nigral and cortical glutamate outflow by NT and the enhancement of NMDA receptor function by a possible NTS1/NMDA interaction that involves the activation of protein kinase C may favour the depolarization of NTS1 containing neurons and the entry of calcium [3]. These results strengthen the hypothesis that NT may be involved in the amplification of glutamate-induced neurotoxicity in mesencephalic dopamine and cortical neurons. The possible increase in NT levels in the basal ganglia under pathological conditions leading to the NTS1 enhancement of glutamate signalling may contribute to the neurodegeneration of the nigrostriatal dopaminergic neurons found in Parkinson's disease, especially in view of the high density of NTS1 receptors in these neurons. In line with this hypothesis, results from preliminary behavioural, functional and biochemical experiments [4] suggest a putative neuroprotective effect following the systemic administration of the selective NTS1 antagonist SR48692 in an in vivo animal model of Parkinson's disease (unilateral nigral 6-hydroxydopamine induced lesion of the nigrostriatal pathway). Thus, the use of selective NTS1 antagonists together with conventional drug treatments could provide a novel therapeutic approach for treatment of Parkinson's disease and other neurodegenerative pathologies [5].
 
[1] Quirion (1983) Interactions between neurotensin and dopamine in the brain: an overview. Peptides 4, 609-615.
[2] Antonelli et al. (2007a) Receptor-receptor interactions as studied with microdialysis. Focus on NTR/D2 interactions in the basal ganglia. J Neural Transm 114, 105-113.
[3] Antonelli et al. (2007b) Neurotensin receptor mechanisms and its modulation of glutamate transmission in the brain: relevance for neurodegenerative diseases and their treatment.Prog Neurobiol83,:92-109.
[4] Ferraro (2008) Neurotensin receptors as modulators of glutamatergic transmission. Brain Res Rev 58, 365-373.
[5] Ferraro (2009) Emerging evidence for neurotensin receptor 1 antagonists as novel pharmaceutics in neurodegenerative disorders. Mini Rev Med Chem 9, 1429-1438.