Amelioration of Both Central and Peripheral Neuropathy in Mouse Models of Type 1 and Type 2 Diabetes by the Neurogenic Molecule NSI-189

Abstract

While peripheral neuropathy is the most common complication of long-term diabetes, cognitive deficits associated with encephalopathy and myelopathy also occur. Diabetes is a risk factor for Alzheimer disease (AD) and increases the risk of progression from mild cognitive impairment to AD. The only current recommendation for preventing or slowing the progression of peripheral neuropathy is to maintain close glycemic control, while there is no recommendation for central nervous system disorders. NSI-189 is a new chemical entity that when orally administered promotes neurogenesis in the adult hippocampus, increases hippocampal volume, enhances synaptic plasticity, and reduces cognitive dysfunction. To establish the potential for impact on peripheral neuropathy, we first showed that NSI-189 enhances neurite outgrowth and mitochondrial functions in cultured adult rat primary sensory neurons. Oral delivery of NSI-189 to murine models of type 1 (female) and type 2 (male) diabetes prevented multiple functional and structural indices of small and large fiber peripheral neuropathy, increased hippocampal neurogenesis, synaptic markers and volume, and protected long-term memory. NSI-189 also halted progression of established peripheral and central neuropathy. NSI-189, which is currently in clinical trials for treatment of major depressive disorder, offers the opportunity for the development of a single therapeutic agent against multiple indices of central and peripheral neuropathy.

Muscarinic Toxin 7 Signals Via Ca2+/Calmodulin-Dependent Protein Kinase Kinase β to Augment Mitochondrial Function and Prevent Neurodegeneration

“…b Corneal nerve density (SBNP) was measured by confocal microscopy in control or oxaliplatin-treated (CIPN) female Swiss Webster mice before (pre) and 2 weeks after (+MT7) daily delivery of MT7 to one eye (30 μl of 25 ng/ml solution), Monday-Friday, for 2 weeks. In this study, the SBNP was measured by tracing all nerves and recording total pixels/ image area [58]. Data are group mean + SEM of N = 7-9/group.…”

“…Corneal nerves of the sub-basal nerve plexus were imaged in anesthetized mice using a Heidelberg Retina Tomograph 3 with Rostock Cornea Module (Heidelberg Engineering, Heidelberg Germany) as described elsewhere [57]. Corneal nerve density was measured in 5 consecutive images (2-μm intervals) of the sub-basal nerve plexus (SBNP) between the corneal epithelium and stroma and quantified either as occupancy using an 8 × 8 grid layered onto each image [56] or as pixel density following tracing of all visible nerves using ImageJ software [58].…”

Enhancement of Mitochondrial Function by the Neurogenic Molecule NSI-189 Accompanies Reversal of Peripheral Neuropathy and Memory Impairment in a Rat Model of Type 2 Diabetes

“…We recently reported that NSI-189 prevented and reversed memory impairments, restored hippocampal neurogenesis, and enhanced expression of synaptic markers in the CNS of type 1 or type 2 diabetic mice while concurrently ameliorating peripheral neuropathy [16]. Intriguingly, NSI-189 applied to sensory neurons in vitro both enhanced neurite outgrowth and stimulated maximal and spare respiratory capacity [16]. The present study expands investigation of the ability of NSI-189 to stimulate mitochondria and ameliorate indices of CNS and PNS dysfunction in the Zucker diabetic fatty (ZDF) rat model of type 2 diabetes.…”

“…Clinical trials in subject with major depressive disorder (MDD) demonstrated that NSI-189 is safe and had long-lasting antidepressive and procognitive effects [14,15]. We recently reported that NSI-189 prevented and reversed memory impairments, restored hippocampal neurogenesis, and enhanced expression of synaptic markers in the CNS of type 1 or type 2 diabetic mice while concurrently ameliorating peripheral neuropathy [16]. Intriguingly, NSI-189 applied to sensory neurons in vitro both enhanced neurite outgrowth and stimulated maximal and spare respiratory capacity [16].…”

DW14006 as a Direct AMPKα Activator Ameliorates Diabetic Peripheral Neuropathy in Mice

“…Finally, DPN improvement was evaluated by MNCV and sensory sensitivity assays in the current work, although these assays are very potent for DPN study (28,49) according to the Diabetes Complications Consortium guidelines, sensory nerve conduction velocity (SNVC)-related assays should be of high complementation to our work.…”