Therapeutic Effects of Fenofibrate on Diabetic Peripheral Neuropathy by Improving Endothelial and Neural Survival in db/db Mice

Abstract

Neural vascular insufficiency plays an important role in diabetic peripheral neuropathy (DPN). Peroxisome proliferative-activated receptor (PPAR)α has an endothelial protective effect related to activation of PPARγ coactivator (PGC)-1α and vascular endothelial growth factor (VEGF), but its role in DPN is unknown. We investigated whether fenofibrate would improve DPN associated with endothelial survival through AMPK-PGC-1α-eNOS pathway. Fenofibrate was given to db/db mice in combination with anti-flt-1 hexamer and anti-flk-1 heptamer (VEGFR inhibition) for 12 weeks. The db/db mice displayed sensory-motor impairment, nerve fibrosis and inflammation, increased apoptotic cells, disorganized myelin with axonal shrinkage and degeneration, fewer unmyelinated fibers, and endoneural vascular rarefaction in the sciatic nerve compared to db/m mice. These findings were exacerbated with VEGFR inhibition in db/db mice. Increased apoptotic cell death and endothelial dysfunction via inactivation of the PPARα-AMPK-PGC-1α pathway and their downstream PI3K-Akt-eNOS-NO pathway were noted in db/db mice, human umbilical vein endothelial cells (HUVECs) and human Schwann cells (HSCs) in high-glucose media. The effects were more prominent in response to VEGFR inhibition. In contrast, fenofibrate treatment ameliorated neural and endothelial damage by activating the PPARα-AMPK-PGC-1α-eNOS pathway in db/db mice, HUVECs and HSCs. Fenofibrate could be a promising therapy to prevent DPN by protecting endothelial cells through VEGF-independent activation of the PPARα-AMPK-PGC-1α-eNOS-NO pathway.

Diabetic Polyneuropathy in Type 2 Diabetes Mellitus: Inflammation, Oxidative Stress, and Mitochondrial Function

“…The preliminary observational findings in the FDS indicate that fibrates have protective properties against neuropathy, with HR even lower than statins of 0.52 (CI 95% 0.27–0.98) [134]. An experimental study in db/db mice model of diabetic peripheral neuropathy published in 2014 demonstrated that Fenofibrate treatment ameliorated neural and endothelial damage by activating the PPAR α -adenosine monophosphate kinase- (AMPK-) PPAR γ coactivator- (PGC-) 1a-endothelial nitric oxide (eNOS) pathway [142]. Fenofibrate possesses anti-inflammatory, antioxidant, and anti-ischemic properties, and it could have beneficial effects on DPN, but large randomized clinical studies are needed to consider Fenofibrate an adequate treatment for DPN in type 2 DM patients [143].…”

Nuclear Countermeasure Activity of TP508 Linked to Restoration of Endothelial Function and Acceleration of DNA Repair

“…It is now established that even low doses of radiation cause loss of endothelial function and reduced NO signaling, often before any morphological effects can be observed (6–8, 42). It follows that radiation likely affects survival and function of microvascular endothelial cells that supply stem cell niches in bone marrow, intestinal crypts and other tissues (4, 9–11). In vivo studies have shown that microvascular endothelial cell apoptosis begins from 1 to 24 h postirradiation (9, 43) and capillaries begin to disintegrate as early as 1 day postirradiation (44).…”

“…Estimates suggest that thousands of people could die from a small nuclear detonation in any major city. Most deaths would occur from acute radiation syndrome (ARS), caused by high doses of radiation, although a large number of individuals are also likely to die after exposure to lower doses of radiation combined with traumatic injuries and burns [collectively referred to as radiation combined injury (RCI)] (1, 2), or from delayed radiation effects that manifest months later (3, 4). Current therapeutic drug approaches have focused on reversing radiation-induced effects by maintaining the normal levels of leucocytes and platelets or maintaining intestinal crypts (5).…”

“…Recent studies indicate that endothelial function and nitric oxide (NO)-dependent vasodilation are compromised by low doses of radiation, often before any morphological effects can be observed (6–8). Moreover, radiation-induced damage may specifically affect survival and function of microvascular endothelial cells that supply stem cell niches in bone marrow, intestinal crypts and other tissues (4, 9–11). …”

Alternatives to the Streptozotocin-Diabetic Rodent

“…The db/db mouse, like the ZDF rat, is obese and insulin resistant. It develops a severe hyperglycemia and peripheral neuropathy with decreased nerve conduction velocity and morphological changes in peripheral nerves (Cho et al, 2014; Norido, Canella, Zanoni, & Gorio, 1984; Nowicki et al, 2012; Pande et al, 2011; Robertson & Sima, 1980; Shi et al, 2013; Sima & Robertson, 1978). In a study comparing the effect of hyperglycemia in 4-month-old C57BL6 (control), ob/ob, and db/db mice it was found that myelin thickness was significantly reduced in small, medium-sized, and large axons of db/db mice compared with control C57Bl6 mice (Nowicki et al, 2012).…”