Background: Diabetic Neuropathy is one of the most prevalent complications of diabetes. Clinically, Diabetic Peripheral Neuropathy (DPN) is characterized by reduced electrophysiological recordings and sensorimotor deficits which have been correlated with myelin defects in nerve fibers and limited regenerative potential. Oxidative stress emerged as the final key mediator of diabetic complications. Cytochrome P450 (CYPs) enzymes are major contributors which have been shown to mediate diabetes-induced organ injuries. Yet, no studies have investigated their role in DPN.
Methods: We assessed peripheral nerve functionality in a murine model of type 2 diabetes mellitus (T2D) treated with either a potent and selective inhibitor of 20-HETE synthesizing enzyme, HET0016, or with metformin, an AMPK activator. Behavioral, histological, biochemical and molecular assessments were performed.
Results: Hyperglycemia resulted in CYP4A protein upregulation and 20-HETE overproduction in sciatic nerves of diabetic animals which correlated with alterations in myelin protein levels culminating in sensorimotor deficits. Elevated 20-HETE levels were concurrent with increased ROS production. This was paralleled by AMPK inactivation in addition to alterations in Beclin-1 and LC3B levels. Interestingly, 20-HETE synthesizing enzyme inhibition via HET0016 was shown to normalize myelin protein profiles, p-AMPK levels, ROS production and autophagic defenses, restoring sensorimotor function in diabetic animals. Of interest, mice treated with metformin exhibited a decrease in CYP4A protein expression as well as in 20-HETE levels. Similarly, metformin treatment withdrew the injurious effect of diabetes on Schwann cells and attenuated peripheral neuropathy.
Conclusion: Our study suggest that hyperglycemia leads to oxidative injury via CYP4A alteration and AMPK inactivation, altering autophagy which compromises myelin integrity and peripheral nerve functionality.
M. Haddad: None. S. Eid: None. A.A. Eid: None.
American University of Beirut