Neurokinin‐3 peptide instead of neurokinin‐1 synergistically exacerbates kainic acid‐inducing degeneration of neurons in the substantia nigra of mice

Abstract

Neurokinin peptides neurokinin‐1 (NK1), neurokinin‐3 (NK3), and related receptors are abundantly distributed in the substantia nigra (SN) and evidenced by their possible roles in the Parkinson’s disease. Differential intervention roles of NK3 on kainic acid (KA)‐induced neuronal injury in the SN of mice were thus in vitro and in vivo studied by Fluoro‐Jade C (FJC) staining, immunohistochemistry to tyrosine hydroxylase (TH) or phospho‐NMDA receptor, and 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay. It revealed that (i) in contrast to protective effect of NK1 agonist septide that reduced FJC‐positive degenerative neurons and lesion volume insulted by KA, NK3 agonist senktide significantly increased FJC‐positive ones and lesion volume, and this effect was sufficiently reversed by NK3 antagonist SB218795; (ii) similarly, senktide reduced TH‐positive neurons and this effect was antagonized by SB218795, but septide increased TH‐positive ones; (iii) mechanistic observation showed differential influences of NK1 and NK3 agonists on phosphorylated‐NMDA receptor subunit 1 (phospho‐NMDAR1) and glial fibrillary acidic protein‐expressing astrocytes, i.e. senktide enhanced of NMDA receptor phosphorylation and astrocyte activity, while septide reduced NMDA receptor phosphorylation and astrocytic response; (iv) cell culture further confirmed the exacerbating effect of NK3 agonist on KA‐induced lesion of nigral cells or dopaminergic neurons, in which administration of senktide alone did not show significant cell toxicity. This study presents new evidence that neurokinin NK3 instead of NK1 synergistically exacerbate excitotoxic neuronal degeneration in the SN in a dose‐dependent manner and possibly through modulation of NMDA receptor phosphorylation and astrocyte activity, suggesting their potential significance in novel pharmaceutical therapy against Parkinson’s disease.

The proNGF-p75NTR-Sortilin Signalling Complex as New Target for the Therapeutic Treatment of Parkinsons Disease

“…In contrast, more cholinergic neurons survived in the basal forebrain regions of p75NTR gene knock-out mice [21]. Moreover, we first identified p75NTR expression in the nigral dopamine neurons, and KA-induced upregulation of p75NTR mRNA and protein along with massive neuronal degeneration of the substantia nigra of adult rats [7,22]. In normal adult rats, p75NTR was expressed in about 47% of tyrosine hydroxylase (TH)-positive neurons of the substantia nigra pars compacta, and p75-positive neurons were much less distributed in the substantia nigra pars reticularis.…”

“…Our recent studies further indicated that dynamic p75NTR expression also occurred in substantia nigra in the MPTP mouse model (personal unpublished data). Upregulation of p75NTR was coincident with progressive neuronal degeneration in the substantia nigra indicated by fluorojade dyes, which specifically stain the neuronal degeneration in the basal ganglia or CNS, suggesting that p75NTR signalling might be involved in neuronal degeneration in substantia nigra in the MPTP model of PD [22][23][24][25][26][27].…”

Up-regulation of d-serine Might Induce GABAergic Neuronal Degeneration in the Cerebral Cortex and Hippocampus in the Mouse Pilocarpine Model of Epilepsy

“…The key finding in our present study is up-regulation of D-serine in the GABAergic neurons or in degenerating neurons of brains after moderate seizures. And, enhancing phosphorylation of NMDA receptor was also coincided with D-serine increase in brains of the pilocarpine model, suggesting that D-serine may trigger NMDA over-activation and neuronal excitotoxic damage under epileptic condition [4,8,26].…”

“…This study has further demonstrated significant up-regulation of D-serine in a portion of GABAergic neurons, or in most of degenerating neurons in the cerebral cortex and hippocampus. Moreover, it revealed that D-serine-positive neurons reached peak levels earlier than that of massive neuronal death, and they were accompanied by enhancing phosphorylation of NMDA receptors that may reflect activation state of NMDA receptors [26]. Taken together, this study has provided new evidence that abnormal increase in D-serine generation might induce degenerative death of GABAergic neurons in the pilocarpine model through NMDA receptor over-activation and excitotoxic mechanisms, and may also be involved in early pathogenesis and recurrent seizure development of chronic epilepsy [1,11,14,[27][28][29].…”

“…The pNMDAR1 immunohistochemistry was applied in brain sections of pilocarpine-treated mice and controls to detect phosphorylation of NMDA receptor, which may reflect activation state of NMDA receptors in neurons [26]. Large numbers of pNMDAR1-positive neurons were observed in the cerebral cortex and hippocampus in the pilocarpine model.…”