The Neurogenic Effects of Exogenous Neuropeptide Y: Early Molecular Events and Long-Lasting Effects in the Hippocampus of Trimethyltin-Treated Rats

Abstract

Modulation of endogenous neurogenesis is regarded as a promising challenge in neuroprotection. In the rat model of hippocampal neurodegeneration obtained by Trimethyltin (TMT) administration (8 mg/kg), characterised by selective pyramidal cell loss, enhanced neurogenesis, seizures and cognitive impairment, we previously demonstrated a proliferative role of exogenous neuropeptide Y (NPY), on dentate progenitors in the early phases of neurodegeneration. To investigate the functional integration of newly-born neurons, here we studied in adult rats the long-term effects of intracerebroventricular administration of NPY (2 µg/2 µl, 4 days after TMT-treatment), which plays an adjuvant role in neurodegeneration and epilepsy. Our results indicate that 30 days after NPY administration the number of new neurons was still higher in TMT+NPY-treated rats than in control+saline group. As a functional correlate of the integration of new neurons into the hippocampal network, long-term potentiation recorded in Dentate Gyrus (DG) in the absence of GABAA receptor blockade was higher in the TMT+NPY-treated group than in all other groups. Furthermore, qPCR analysis of Kruppel-like factor 9, a transcription factor essential for late-phase maturation of neurons in the DG, and of the cyclin-dependent kinase 5, critically involved in the maturation and dendrite extension of newly-born neurons, revealed a significant up-regulation of both genes in TMT+NPY-treated rats compared with all other groups. To explore the early molecular events activated by NPY administration, the Sonic Hedgehog (Shh) signalling pathway, which participates in the maintenance of the neurogenic hippocampal niche, was evaluated by qPCR 1, 3 and 5 days after NPY-treatment. An early significant up-regulation of Shh expression was detected in TMT+NPY-treated rats compared with all other groups, associated with a modulation of downstream genes. Our data indicate that the neurogenic effect of NPY administration during TMT-induced neurodegeneration involves early Shh pathway activation and results in a functional integration of newly-generated neurons into the local circuit.

Systemic Central Nervous System (CNS)-targeted Delivery of Neuropeptide Y (NPY) Reduces Neurodegeneration and Increases Neural Precursor Cell Proliferation in a Mouse Model of Alzheimer Disease

“…Many neurodegenerative diseases, including AD, manifest with alterations in circadian rhythms (4,69,70) and one prominent clinical feature of AD is weight loss correlating with disease severity (71). In fact, several studies have reported that one of the earliest symptoms of AD, manifesting in pre-clinical mild cognitive impairment, may be early weight loss (72)(73)(74)(75).…”

Cellular targets for neuropeptide Y-mediated control of adult neurogenesis

“…Exogenous NPY has been administered in the Trimethyltin (TMT)-induced model of hippocampal neurodegeneration and temporal lobe epilepsy, in which selective pyramidal cell loss in hippocampal CA1/CA3 subfields (Geloso et al, 1996 , 1997 ), reactive astrogliosis and microglial activation (for review see Geloso et al, 2011 ; Corvino et al, 2013 ; Lattanzi et al, 2013 ) are associated with injury-induced neurogenesis (Corvino et al, 2005 ). NPY injection in TMT-treated rats results in long-term effects on the hippocampal neurogenic niche, culminating in the functional integration of newly generated neurons into the local circuit (Corvino et al, 2012 , 2014 ). The early events following NPY administration are characterized by the up-regulation of genes involved in different aspects of NSC dynamics.…”

“…The early events following NPY administration are characterized by the up-regulation of genes involved in different aspects of NSC dynamics. In particular, Noggin , which participates in self-renewal processes (Bonaguidi et al, 2008 ), Sox-2 and Sonic hedgehog , both involved in the establishment and maintenance of the hippocampal niche (Favaro et al, 2009 ), NeuroD1 , which regulates differentiation and maturation processes (Roybon et al, 2009 ), Doublecortin , a driver of neuroblast migration (Nishimura et al, 2014 ) and brain-derived neurotrophic factor (BDNF), which is involved in different aspects of dentate neurogenesis (Noble et al, 2011 ), have all been reported to be significantly modulated within the first 24 h following treatment with NPY (Corvino et al, 2012 , 2014 ). These findings suggest that in vivo NPY administration, in association with the peculiar changes in the microenvironment induced by the ongoing neurodegeneration, may trigger a complex mechanism that goes beyond a mere proliferative effect.…”

Effect of Trimethyltin Chloride on Slow Vacuolar (SV) Channels in Vacuoles from Red Beet (Beta vulgaris L.) Taproots

“…Trimethyltin chloride (Met 3 SnCl), studied in this work, is well known mainly as a potent neurotoxin. It triggers many neurodegenerative processes, including loss of neurons [ 44 – 46 ], as well as other degenerative membrane processes [ 47 ]. Trimethyltin has been also shown to decrease intracellular pH, open K + channels and directly inhibit the activity of H + /K + -ATPase in renal intercalated cells [ 44 ].…”