Early vs. late intervention of high fat/low dose streptozotocin treated C57Bl/6J mice with enalapril, α-lipoic acid, menhaden oil or their combination: Effect on diabetic neuropathy related endpoints

Neuropharmacology. 2017 Apr;116:122-131. doi: 10.1016/j.neuropharm.2016.12.022. Epub 2016 Dec 23.


We have previously demonstrated that enalapril, α-lipoic acid and menhaden (fish) oil has potential as a treatment for diabetic peripheral neuropathy. In this study we sought to determine the efficacy of these treatments individually or in combination on multiple neuropathic endpoints in a high fat fed low dose streptozotocin treated mouse, a model of type 2 diabetes, following early or late intervention. Four or twelve weeks after the onset of hyperglycemia, diabetic mice were treated with enalapril, α-lipoic acid, menhaden oil or their combination for 12 weeks. Afterwards, endpoints including glucose tolerance, motor and sensory nerve conduction velocity, thermal nociception, and intraepidermal and cornea nerve fiber density was determined. Glucose clearance was impaired in diabetic mice and significantly improved only with combination treatment and early intervention. Diabetes caused steatosis, slowing of motor and sensory nerve conduction velocity, thermal hypoalgesia and reduction in intraepidermal and cornea nerve fiber density. Treating diabetic mice with enalapril, α-lipoic acid or menhaden oil partially protected diabetic mice from these deficits, whereas the combination of these three treatments was more efficacious following early or late intervention. These studies suggest that a combination therapy may be more effective for treating neural complications of type 2 diabetes.

Keywords: Corneal nerves; Diabetic peripheral neuropathy; Enalapril; Enalapril maleate (PubChem CID: 5388961); Menhaden oil; Type 2 diabetes; α-Lipoic acid; α-Lipoic acid (PubChem CID: 864).

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Acute Disease
  • Animals
  • Chronic Disease
  • Diabetes Mellitus, Experimental / drug therapy*
  • Diabetes Mellitus, Experimental / pathology
  • Diabetes Mellitus, Experimental / physiopathology
  • Diabetic Neuropathies / drug therapy*
  • Diabetic Neuropathies / pathology
  • Diabetic Neuropathies / physiopathology
  • Drug Therapy, Combination
  • Enalapril / pharmacology*
  • Fish Oils / pharmacology*
  • Hypoglycemic Agents / pharmacology*
  • Male
  • Mice, Inbred C57BL
  • Nerve Regeneration / drug effects
  • Nerve Regeneration / physiology
  • Neuroprotective Agents / pharmacology
  • Streptozocin
  • Thioctic Acid / pharmacology*
  • Time Factors


  • Fish Oils
  • Hypoglycemic Agents
  • Neuroprotective Agents
  • Menhaden oil
  • Streptozocin
  • Enalapril
  • Thioctic Acid