Coenzyme Q10 prevents peripheral neuropathy and attenuates neuron loss in the db ⁻ /db ⁻ mouse, a type 2 diabetes model

Abstract

Diabetic peripheral neuropathy (DPN) is the most common complication in both type 1 and type 2 diabetes. Here we studied some phenotypic features of a well-established animal model of type 2 diabetes, the leptin receptor-deficient db − /db − mouse, and also the effect of long-term (6 mo) treatment with coenzyme Q10 (CoQ10), an endogenous antioxidant. Diabetic mice at 8 mo of age exhibited loss of sensation, hypoalgesia (an increase in mechanical threshold), and decreases in mechanical hyperalgesia, cold allodynia, and sciatic nerve conduction velocity. All these changes were virtually completely absent after the 6-mo, daily CoQ10 treatment in db − /db − mice when started at 7 wk of age. There was a 33% neuronal loss in the lumbar 5 dorsal root ganglia (DRGs) of the db − /db − mouse versus controls at 8 mo of age, which was significantly attenuated by CoQ10. There was no difference in neuron number in 5/6-wk-old mice between diabetic and control mice. We observed a strong down-regulation of phospholipase C (PLC) β3 in the DRGs of diabetic mice at 8 mo of age, a key molecule in pain signaling, and this effect was also blocked by the 6-mo CoQ10 treatment. Many of the phenotypic, neurochemical regulations encountered in lumbar DRGs in standard models of peripheral nerve injury were not observed in diabetic mice at 8 mo of age. These results suggest that reactive oxygen species and reduced PLCβ3 expression may contribute to the sensory deficits in the late-stage diabetic db − /db − mouse, and that early long-term administration of the antioxidant CoQ10 may represent a promising therapeutic strategy for type 2 diabetes neuropathy.is a debilitating complication of both type 1 and type 2 diabetes, affecting up to 50% of diabetes patients (1-5). DPN can be observed early in human diabetes (6, 7). Early neurophysiological studies indicated that at initial stages of the illness, the severity of the polyneuropathy was similar in type 1 and type 2 diabetes patients (8). However, more recent studies showed distinct differences both in humans and rodent models. Thus, progressive axonal atrophy and loss are more serious in type 1 diabetes, which in contrast to type 2 shows nodal and paranodal degenerative changes, as well as more severe downstream effects on neuroskeletal and adhesive proteins (9).In type 1 and type 2 diabetes, many patients initially experience painful diabetic neuropathy, allodynia, which subsides and then is replaced by loss of sensation, hypoalgesia (5, 10, 11). A similar course of disease has been noted in the db /db− mouse, just one of many animal models of diabetes (SI Text), has since then been extensively studied as a particularly robust model for type 2 DPN (14).Previous studies of mammalian DPN models have reported a decrease in impulse conduction velocity (CV) in several peripheral nerves, interpreted as being caused by a reduction in number of large or medium-sized axons (15-20), demyelination (18,19,(21)(22)(23), or axon shrinkage/atrophy (24, 25). Unmyelinated and myelinated fibers in the skin a...

Effect of coenzyme Q10 on spinal cord ischemia-reperfusion injury

“…5 More recently, it was found that CoQ 10 is protective against diabetic neuropathy in animal diabetes models. 19 Our finding that the groups treated with CoQ 10 showed significantly improved motor function was consistent with these reports.…”

The role of miR-146a in dorsal root ganglia neurons of experimental diabetic peripheral neuropathy

“…In a model of streptotozin (STZ)-treated rats, Zochodne et al reported no significant changes in DRG neuron number even 12 months after STZ (Zochodne et al, 2001). However, a recent study showed approximately 33% loss of DRG neurons in 8 month old db/db mice (Shi et al, 2013). In the present study, we found an increase in caspase-3, a protein involved in apoptotic cell death, immunoreactivity in DRG neurons of 24 week old db/db mice.…”

Physiology, Signaling, and Pharmacology of Galanin Peptides and Receptors: Three Decades of Emerging Diversity

“…These models include partial sciatic nerve transection (Ma and Bisby, 1997), tibial transection (Hofmann et al, 2003;Garry et al, 2005), nerve crush/pinch (Villar et al, 1991;Xu et al, 2012b), and chronic nerve constriction (Villar et al, , 1991Nahin et al, 1994;Ma and Bisby, 1997;Shi et al, 1999), in which it has been suggested the extent of galanin upregulation is inversely proportional to the development of pain behavior Liu and Hökfelt, 2000) and single ligature nerve constriction (Coronel et al, 2008), partial sciatic or saphenous nerve ligation (Hulse et al, 2008), photochemically-induced ischemic nerve injury (Hao et al, 1999;Shi et al, 1999), spared nerve injury (Holmes et al, 2003), spinal nerve ligation (Fukuoka et al, 1998;Honore et al, 2000), the cisplatin model of neurotoxicity (Barajon et al, 1996), as well as after skin incision, which is preceded by inflammation (Peters et al, 2005;Hill et al, 2010). In contrast, galanin does not appear to increase in models of painful diabetic neuropathy (Zochodne et al, 2001;Burnand et al, 2004;Shi et al, 2013). After nerve injury, galanin is also increased in trigeminal (Zhang et al, 1996) and superior cervical ganglia , which may have implications in pain modulation.…”