Effect of insulin and an erythropoietin-derived peptide (ARA290) on established neuritic dystrophy and neuronopathy in Akita (Ins2Akita) diabetic mouse sympathetic ganglia

Abstract

The Akita mouse is a robust model of diabetic autonomic neuropathy which develops severe diabetes following beta cell death, which occurs reproducibly at 3-4 weeks of age, and maintains the diabetic state without therapy for as long as 11 additional months. Neuritic dystrophy and neuronopathy involving prevertebral sympathetic superior mesenteric and celiac ganglia begin to develop within the first two months of onset of diabetes and are progressive with time. We have examined the effect of insulin implants resulting in normoglycemia and injections of ARA290, a small erythropoietin peptide which has no effect on glycemic parameters, on the reversal of established neuritic dystrophy and neuronopathy. We have found that 4 weeks of insulin therapy beginning at 2 months of diabetes resulted in normalization of blood glucose, body weight and HbA1c. Insulin therapy successfully reversed established neuritic dystrophy and neuronopathy to control levels. Numbers of sympathetic neurons were not significantly changed in either 3 month diabetic or insulin treated Akita mice. Treatment with ARA290 for 7 weeks beginning at 4 months of diabetes did not result in altered metabolic severity of diabetes as measured by blood glucose, body weight or HbA1c levels. ARA290 treatment was able to decrease neuritic dystrophy by 55-74% compared to untreated diabetics or in comparison to a separate group of diabetic animals representing the 4 month treatment onset point. Surprisingly, there was no effect of ARA290 on ganglionic neuron number or ongoing neuronopathy (pale/degenerating neurons) in diabetic Akita mice during this time period. The development of neuroprotective EPO-like peptides may provide a possible future therapy for this debilitating complication of diabetes; however, it appears that discrete elements may be differentially targeted by the diabetic state and may require selective therapy.

Flipping the molecular switch for innate protection and repair of tissues: Long-lasting effects of a non-erythropoietic small peptide engineered from erythropoietin

“…pHBSP is highly effective at preventing clinically relevant lesions of diabetic retinopathy, when administered for 1 month at 6 months after the induction of diabetes, dampening microglia activation and associated pro-inflammatory cytokine expression (McVicar et al, 2011). In a mouse model of diabetic autonomic neuropathy, treatment with pHBSP for 7 weeks decreased neuritic dystrophy, thus further confirming its neuroprotective effects (Schmidt et al, 2011). Very recently, we demonstrated that the chronic administration of pHBSP protects against the metabolic abnormalities, including insulin resistance, caused by a diet containing high concentrations of both fat and sugar.…”

Delayed Administration of Pyroglutamate Helix B Surface Peptide (pHBSP), a Novel Nonerythropoietic Analog of Erythropoietin, Attenuates Acute Kidney Injury

“…These regions do not contain lysine and, therefore, are not modified by carbamylation of EPO, a procedure that produces a tissue-protective compound that is unable to bind to the classic EPO receptor (11). Subsequent studies have since identified that the novel tissue-protective peptide, pHBSP, can confer protection in a number of disease models (29)(30)(31)(32)(33)(34)(35)(36)(37). The interesting aspect of pHBSP is that it has many of the pleiotropic effects of EPO.…”

Cibinetide Improves Corneal Nerve Fiber Abundance in Patients With Sarcoidosis-Associated Small Nerve Fiber Loss and Neuropathic Pain

“…5 IRR activation promotes tissue protection and repair in a wide variety of preclinical models, 5 including neuropathy. [6][7][8] Cibinetide (ARA 290; helix B surface peptide) is a novel 11 amino acid peptide with high affinity and selectivity for the IRR. 9 Despite a short plasma half-life, cibinetide triggers sustained biological effects when concentrations exceed the low nanomolar affinity of the receptor.…”

“…5 Notably, in a mouse model of diabetic SNFL, daily administration of cibinetide reversed neuronal dystrophy. 7 In neuropathic states the transient receptor potential vanilloid-1 (TRPV1) ion channel, a key integrator of nociception and neurogenic inflammation, undergoes upregulation and sensitization in peripheral small nerve fibers and central pain pathways. Recent data demonstrate that cibinetide antagonizes the TRPV1 channel of small nerve fibers and relieves mechanical hypersensitivity.…”