Nasal Colivelin Treatment Ameliorates Memory Impairment Related to Alzheimer's Disease

Abstract

Humanin (HN) and its derivatives, such as Colivelin (CLN), suppress neuronal death induced by insults related to Alzheimer's disease (AD) by activating STAT3 in vitro. They also ameliorate functional memory impairment of mice induced by anticholinergic drugs or soluble toxic amyloid-b (Ab) in vivo when either is directly administered into the cerebral ventricle or intraperitoneally injected. However, the mechanism underlying the in vivo effect remains uncharacterized. In addition, from the standpoint of clinical application, drug delivery methods that are less invasive and specific to the central nervous system (CNS) should be developed. In this study, we show that intranasally (i.n.) administered CLN can be successfully transferred to CNS via the olfactory bulb. Using several behavioral tests, we have demonstrated that i.n. administered CLN ameliorates memory impairment of AD models in a dose-responsive manner. Attenuation of AD-related memory impairment by HN derivatives such as CLN appears to be correlated with an increase in STAT3 phosphorylation levels in the septohippocampal region, suggesting that anti-AD activities of HN derivatives may be mediated by activation of STAT3 in vivo as they are in vitro. We further demonstrate that CLN treatment inhibits an Ab induced decrease in the number of choline acetyltransferase (ChAT)-positive neurons in the medial septum. Combined with the finding that HN derivatives upregulate mRNA expression of neuronal ChAT and vesicular acetylcholine transporter (VAChT) in vitro, it is assumed that CLN may ameliorate memory impairment of AD models by supporting cholinergic neurotransmission, which is at least partly mediated by STAT3-mediated transcriptional upregulation of ChAT and VAChT.

Humanin Inhibits Neuronal Cell Death by Interacting with a Cytokine Receptor Complex or Complexes Involving CNTF Receptor α/WSX-1/gp130

“…Insulin-like growth factor-binding protein-3 enhances HN rescue activity from A␤ toxicity, whereas HN inhibited insulin-like growth factor-binding protein-3-induced apoptosis in human glioblastoma-A172 (Ikonen et al, 2003). In addition, multiple groups have demonstrated that HN derivatives inhibited memory impairment of AD model animals (Mamiya and Ukai, 2001;Krejcova et al, 2004;Chiba et al, 2005;Yamada et al, 2008), including transgenic mice expressing familial AD-causing genes (Chiba et al, 2009).…”

Ginsenoside Re and Rd Enhance the Expression of Cholinergic Markers and Neuronal Differentiation in Neuro-2a Cells

“…8) This implies that the increase of the ChAT level in cholinergic neurons plays a critical role in cognition enhancement and thus the cholinergic gene locus "VAChT/ChAT" can be a putative target for therapeutic approaches on AD. [9][10][11] Several studies reported that ginsenosides (i.e., Rg1 and Rb1) isolated from ginseng are responsible for ginseng's effects on the central nervous system (CNS) and the peripheral nervous system. 12,13) The objective of this study is to investigate whether five representative ginsenosides (Rb1, Re, Rd, Rg1, and Rg3) have beneficial effects on the cholinergic system and also to examine the possible mechanisms of the most active ginsenosides.…”

Neurotrophic Peptides: Potential Drugs for Treatment of Amyotrophic Lateral Sclerosis and Alzheimer’s disease

“…Humanin was found to provide neuroprotection against AD-related insults such as Aβ neurotoxicity *75]. The JAK2/STAT3 signaling pathway showed importance in colivelin neuroprotection against AD-related memory loss [78][79][80]. An in vivo study found that colivelin has more potent neuroprotective effects than humanin and ADNF-9 have when tested against Aβ neurotoxicity *73].…”