Diabetes
 2019
DOI: 10.2337/db19-0271
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Amelioration of Both Central and Peripheral Neuropathy in Mouse Models of Type 1 and Type 2 Diabetes by the Neurogenic Molecule NSI-189

Corinne G. Jolivalt
1
,
Alexandra Marquez
2
,
David M. Quach3
et al.

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 … Show more

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Cited by 11 publications

(17 citation statements)
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“…Impaired short-term memory in ZDF rats was accompanied by reduced expression of synaptic proteins and is consistent with reports of impaired synaptic plasticity in the brain of other rodent models of type 1 and type 2 diabetes [42][43][44]. Supporting its procognitive properties in both animal models [16,23,45] and humans with MDD [14,15], NSI-189 treatment reversed an established memory deficit in ZDF rats and efficacy was maintained for 12 weeks. This was accompanied by 9 Journal of Diabetes Research protection or normalization of hippocampal CA3 volume and a significant increase in expression of synaptic plasticity marker proteins.…”
Section: Discussionsupporting
confidence: 89%
“…There was no evidence of drug tolerance 6 Journal of Diabetes Research as efficacy of NSI-189 was maintained for the study duration. These findings extend prior data obtained in mouse models of diabetes [16] and emphasize that NSI-189 shows efficacy in multiple species. The ability of NSI-189 to reverse established neuropathy is encouraging, as intervention is the most likely scenario for translation to clinical use, particularly as large fiber conduction slowing and pain are currently accepted readouts for therapeutic efficacy in clinical trials [29].…”
Section: Discussionsupporting
confidence: 88%
“…The most striking divergence from anticipated data was our observation that nerve density in the corneal subbasal plexus was significantly increased in 10-month-old ZDF rats. This increase contrasts with the typical decrease in corneal nerve density seen in models of type 1 diabetes [16,21,36,37], in a model of late type 2 diabetes resulting from feeding a high fat diet combined with a low dose of STZ to induce insulin resistance, impede insulin secretion, and produce marked hyperglycemia [38], and in diabetic humans [39]. We are not aware of prior reports of corneal nerve density in ZDF rats.…”
Section: Discussionmentioning
confidence: 69%
“…We are not aware of prior reports of corneal nerve density in ZDF rats. However, there was no corneal nerve loss in the equivalent db/ db mouse model of type 2 diabetes [16]. It is plausible that normal or elevated corneal nerve density in these models results from hyperinsulinemia in the earlier stages of diabetes despite the decrease to similar levels as control in the later stage, as insulin has direct neuritogenic effects on sensory nerves [34] and prevents corneal nerve loss when applied to the eye of insulin-deficient diabetic mice [21].…”
Section: Discussionmentioning
confidence: 94%
“…We previously showed that NSI-189 promoted neurite outgrowth when added to cultured primary sensory neurons derived from normal and type 1 diabetic rats and also dosedependently increased maximal and spare respiratory capacity [16], suggesting mitochondrial activation. We therefore extended our investigations to tissue obtained from diabetic rats treated with NSI-189 in vivo.…”
Section: Discussionmentioning
confidence: 95%
See 4 more Smart Citations
Exaggerated anticipatory anxiety is common in social anxiety disorder (SAD). Neuroimaging studies have revealed altered neural activity in response to social stimuli in SAD, but fewer studies have examined neural activity during anticipation of feared social stimuli in SAD. The current study examined the time course and magnitude of activity in threat processing brain regions during speech anticipation in socially anxious individuals and healthy controls (HC). Method Participants (SAD n = 58; HC n = 16) underwent functional magnetic resonance imaging (fMRI) during which they completed a 90s control anticipation task and 90s speech anticipation task.
show abstract
“…Impaired short-term memory in ZDF rats was accompanied by reduced expression of synaptic proteins and is consistent with reports of impaired synaptic plasticity in the brain of other rodent models of type 1 and type 2 diabetes [42][43][44]. Supporting its procognitive properties in both animal models [16,23,45] and humans with MDD [14,15], NSI-189 treatment reversed an established memory deficit in ZDF rats and efficacy was maintained for 12 weeks. This was accompanied by 9 Journal of Diabetes Research protection or normalization of hippocampal CA3 volume and a significant increase in expression of synaptic plasticity marker proteins.…”
Section: Discussionsupporting
confidence: 89%
“…There was no evidence of drug tolerance 6 Journal of Diabetes Research as efficacy of NSI-189 was maintained for the study duration. These findings extend prior data obtained in mouse models of diabetes [16] and emphasize that NSI-189 shows efficacy in multiple species. The ability of NSI-189 to reverse established neuropathy is encouraging, as intervention is the most likely scenario for translation to clinical use, particularly as large fiber conduction slowing and pain are currently accepted readouts for therapeutic efficacy in clinical trials [29].…”
Section: Discussionsupporting
confidence: 88%
“…The most striking divergence from anticipated data was our observation that nerve density in the corneal subbasal plexus was significantly increased in 10-month-old ZDF rats. This increase contrasts with the typical decrease in corneal nerve density seen in models of type 1 diabetes [16,21,36,37], in a model of late type 2 diabetes resulting from feeding a high fat diet combined with a low dose of STZ to induce insulin resistance, impede insulin secretion, and produce marked hyperglycemia [38], and in diabetic humans [39]. We are not aware of prior reports of corneal nerve density in ZDF rats.…”
Section: Discussionmentioning
confidence: 69%
“…We are not aware of prior reports of corneal nerve density in ZDF rats. However, there was no corneal nerve loss in the equivalent db/ db mouse model of type 2 diabetes [16]. It is plausible that normal or elevated corneal nerve density in these models results from hyperinsulinemia in the earlier stages of diabetes despite the decrease to similar levels as control in the later stage, as insulin has direct neuritogenic effects on sensory nerves [34] and prevents corneal nerve loss when applied to the eye of insulin-deficient diabetic mice [21].…”
Section: Discussionmentioning
confidence: 94%
“…We previously showed that NSI-189 promoted neurite outgrowth when added to cultured primary sensory neurons derived from normal and type 1 diabetic rats and also dosedependently increased maximal and spare respiratory capacity [16], suggesting mitochondrial activation. We therefore extended our investigations to tissue obtained from diabetic rats treated with NSI-189 in vivo.…”
Section: Discussionmentioning
confidence: 95%
See 3 more Smart Citations
Exaggerated anticipatory anxiety is common in social anxiety disorder (SAD). Neuroimaging studies have revealed altered neural activity in response to social stimuli in SAD, but fewer studies have examined neural activity during anticipation of feared social stimuli in SAD. The current study examined the time course and magnitude of activity in threat processing brain regions during speech anticipation in socially anxious individuals and healthy controls (HC). Method Participants (SAD n = 58; HC n = 16) underwent functional magnetic resonance imaging (fMRI) during which they completed a 90s control anticipation task and 90s speech anticipation task.
show abstract
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