| Parkinson's disease (PD) is one of most common neurodegenerative diseases, which is characterized by serious motor sympotoms such as resting tremor, bradykinesia, rigidity, gait disturbance and postural instability. PD is typically resulted from the massive degenerative death of dopamine neurons in the substantia nigra. Current treatment can not prevent nigral neurons from progressive death and pathogical progress of PD. Previous studies have indicated that glutamate-excitotoxicity may be one of crucial factors implicating in degeneration of nigral neurons and pathogenesis of PD. It is necessary, thus, to investigate novel strategies on preventing nigral dapamine neurons from excitotoxic lesions and improving the treatment of PD.Mammalian neurokinins [NKs] are a family of tachykinin peptides that include substance P (SP; neurokinin-1, NK-1), neurokinin A (SK;NK-2; neurokinin A) and neurokinin B (NK; NK-3; neurokinin B). Their biological functions are mediated by three distinct G-protein coupled neurokinin receptors, namely SP receptor (SPR: NK-1 receptor, NK-1R), neurokinin A receptor (NK-2R) and neurokinin B receptor (NK-3R). Neurokinin peptides and neurokinin receptors are abundantly distributed in the basal ganglia regions and known to significantly interact with neurons of the basal ganglia. Previous evidence has suggested that they may be involved in the regulation of physiological and pathological processes in the basal ganglia circuitry. Further studies should be devoted to elucidate whether neurokinins are involved in modulating glutamate-exitotoxcity and degenerative death of nigral dopamine neurons.Roles of different neurokinins (e.g. NK1, NK3) in regulation of exitotoxicity of nigral dopamine neurons and possible interaction substrate were studied by using primary nigral cell culture and animal models induced by Kainic acid (KA) leison, administration of neuronkinin receptor agonists, Fluoro-Jade B staining, double immunofluorescence, laser scanning confocal microscopy and behavior analysis.Major results are included: (l)Co-expression of glutamate receptor subunits in NK-3R-containing neurons was found in the substantia nigra pars compacta of adult mice. It revealed that majority of NK-3R-immunoreactive neurons (80-100%) overlapped with that of NMDA receptor subunit (NMDAR1), AMPA receptor subunits (GluRl, GluR2, GluR3) and kainite receptor subunit (GluR5/6/7). In contrast, theneurons exhibiting both NK-3R and GluR4-immunoreactivity were hardly detected; (2) Roles of neurokinins in regulating KA-induced excitotoxic lesion of nigral neurons were applied in vitro cell culture. Pretreatment with NK1 receptor agonist septide increased cell activity and numbers of TH-immunopositive neurons, while pretreatment with NK3 receptor agonist senktide decreased cell activity and numbers of TH-positive neurons; (3) Roles of neurokinin agonists in regulating KA-induced excitotoxicity of nigral dopaminergic neurons and motor behavior were perfomed by in vivo animal models. Comparison with that of single KA lesion group, treatment with NK1 receptor agonist septide relieved symptom of turing behavior, decreased numbers of FJB-stained degenerative neurons and increased numbers of TH-immunopositive neurons, while treatment with NK3 receptor agonist senktide aggravated symptom of turing behavior, increased numbers of FJB-stained degenerative neurons and decreased numbers of TH-immunopositive neurons in the substantia nigraWe have concluded: (1) Co-expression of NK-3R and distinct NMDA^ AMPA/KA receptor subunits in the nigral neurons has provided morphological substrate for functional interaction between neurokinins and glutamate receptors, in which the latter may mediate glutamate-excitotoxicity of the nigral dopamine neurons; (2) Intervention effects of neurokinin receptor agonists on exitotoxic lesion of nigral dopamine neurons and motor activity of mice have indicated that neurokinins signal may play important role in the pathogenesis of PD; (3) Different neurokinins had distinct effects on regulation of... |
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