The Differential Roles Of Neurokinin-like Peptides (NK1, NK3) In Modulating Excitotoxic Lesions And Neuronal Survival In The Basal Ganglia (Striatum)

The diseases of neurodegenerative in Center Nervous System(CNS)mainly caused by the lose of neurons in the related lesion nucleus. HD is an autosomal dominant neurodegenerative disorder characterized by involuntary movements (chorea) and cognitive impairment (dementia). The pathological hallmark of HD is the marked atrophy of the striatum consecutive to a massive loss of medium-sized spiny projection neurons. Previous studies have indicated that glutamate-excitotoxicity may be one of crucial factors involved in degeneration of striatum neurons and pathogenesis of HD. It is necessary, thus, to investigate novel strategies on preventing striatum neurons from excitotoxic lesions and searching the new protection strategy.Mammalian neurokinin family is composed of three major members, i.e. substance P (SP;neurokinin-1, NK-1), substance K (SK;neurokinin A;NK-2), and neuromedin K (NK;neurokinin B;NK-3). 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 neurokinins and neurokinin receptors reduced in the PD patient and PD animal model's basal ganglia,which clue us that they may be involved in the regulation of physiological and pathological processes in the basal ganglia circuitry. Barker and Raffa thought that neurokinins are related to neurodegenerative , the change of endoneurokinins may have the important role in neurodegenerative diseases.So further studies should be devoted to elucidate whetherneurokinins are involved in modulating glutamate-exitotoxicity and degenerative death of striatum neurons induced by kainic acid (KA).In this study, the mouse were administrated with KA by intrastriatal injection and neurokinins agonists (NKl agonist septide and NK3 agonist senktide)NK3 antagonist (SB218795) interfere model . Then the lesion was evaluated by Fluoro-Jade B(FJB) stain and NADPH-d histochemistry, double immunofluorescence, laser scanning confocal microscopy and behavior analysis. The results show that:(l)The lesion of striatum neurons induced by KA is close related with glutamate-excitotoxicity.In the KA lesion striatum about 63.7% degenerating neurons double labeled with Glutamate receptor subunit NRl;100% degenerating neurons of the cortex double labled with GluR2/3.(2)Difference neurokinin molecules have different roles :NK1 receptor agonist-septide has neuroprotective role that is decrease the FJB positive cells;NK3 receptor agonist-senktide increase the degeneration neurons of striatum.The FJB cell numbers of each group through Kruskul-Wallis rank sum test,H value is 137.71,p value is <0.0001.Then the SNK-q test shows: a =0.05,besides KA+O.Otygsenktide group and KA+0.02//gsenktide group has no significance,the other groups all have significance.Septide can increase the survive of NOS cells;but senktide decrease the NOS cells.The difference value between injection side and normal side of six groups through completely randomization design ANOVA has significance^ value is 81.47, p value is <0.0001.Then the SNK-q test shows: a =0.05,besides KA+0.02^gsenktide group and KA+O.Ol^gsenktide group has no significance,saline group and KA+Sep group have no significance ,the other groups all have significance.(3) NK3 receptor antagonist SB218795 antagonize the role of NIG receptor agonist-senktide and have the potent neuroprotection. The FJB cell numbers of each group through Kruskul-Wallis rank sum test,H value is 120.74,p value is <0.0001.Then the SNK-q test shows: a =0.05,besides KA+0.02^gsenktide+SB218795 group and KA+ SB218795 group;SB218795 group,DMSO group and saline group have no significance,the other groups all have significance.SB218795 can decrease the degenerative neurons and increase the survive NOSpositive neurons induced by kainic acid. The difference value between injection side and normal side of six groups through completely randomization design ANOVA has dignificance,F value is 30.77, p value is <0.0001.Then the SNK-q test shows: a =0.05,besides KA+0.02/agsenktide+SB218795 group and KA group;KA group and KA+SB218795 group;SB218795 group,DMSO group and saline group have no significance, the other groups all have significance.Taken together with previous studies, the present results have indicated that(l)Neurokinins have close relationship with degenerative diseases of basal ganglia, which may be interact with Glutamate-Glutamate receptor pathway.(2) Difference neurokinin molecules have different roles :NK1 receptor agonist-septide has neuroprotective roles,but NK3 receptor agonist-senktide has the opposite roles.(3)Our NK3 receptor antagonist experience show that NK3 receptor antagonist-SB218795 has the neuroprotective roles.Our results suggested that NK1 and NK3 may serve as the new potential therapeutic intervention targets in the degenerative diseases of basal ganglia.