Poly(ADP-Ribose) Polymerase Inhibition Alleviates Experimental Diabetic Sensory Neuropathy

Abstract

Poly(ADP-ribose) polymerase (PARP) activation is emerging as a fundamental mechanism in the pathogenesis of diabetes complications including diabetic neuropathy. This study evaluated the role of PARP in diabetic sensory neuropathy. The experiments were performed in control and streptozotocin-induced diabetic rats treated with or without the PARP inhibitor 1,5-isoquinolinediol (ISO; 3 mg ⅐ kg ؊1 ⅐ day ؊1 i.p.) for 2 weeks after 2 weeks without treatment. Diabetic rats developed thermal hyperalgesia (assessed by paw-withdrawal and tail-flick tests), mechanical hyperalgesia (von Frey anesthesiometer/rigid filaments and Randall-Sellito tests), tactile allodynia (flexible von Frey filaments), and increased flinching behavior in phases 1 and 2 of the 2% formalin pain test. They also had clearly manifest increase in nitrotyrosine and poly(ADPribose) immunoreactivities in the sciatic nerve and increased superoxide formation (hydroxyethidine method) and nitrotyrosine immunoreactivity in vasa nervorum. ISO treatment alleviated abnormal sensory responses, including thermal and mechanical hyperalgesia and tactile allodynia as well as exaggerated formalin flinching behavior in diabetic rats, without affecting the aforementioned variables in the control group. Poly(ADP-ribose) and, to a lesser extent, nitrotyrosine abundance in sciatic nerve, as well as superoxide and nitrotyrosine formation in vasa nervorum, were markedly reduced by ISO therapy. Apoptosis in dorsal root ganglion neurons (transferase-mediated dUTP nick-end labeling assay) was not detected in any of the groups. In conclusion, PARP activation contributes to early diabetic sensory neuropathy by mechanisms that may include oxidative stress but not neuronal apoptosis.

A peroxynitrite decomposition catalyst counteracts sensory neuropathy in streptozotocin-diabetic mice

“…Clearly manifest tactile allodynia is observed in STZ-diabetic rats Ilnytska et al, 2006) and mice (the present study). The mechanisms of this phenomenon are not well understood.…”

“…Another phenomenon, mechanical hyperalgesia, detected by reduced paw withdrawal thresholds during paw stimulation with rigid von Frey filaments or Randall-Sellito test, has been found clearly manifest in STZ-diabetic and ZDF rats (Cameron et al, 2001a,b;Cotter et al, 2002;Ilnytska et al, 2006;Li et al, 2006), and reversed or alleviated by antioxidants including α-lipoic acid (Cameron et al, 2001a), dimethylthiourea (Cameron et al, 2001b), taurine (Li et al, 2005b) as well as PARP inhibitors . Of interest, STZdiabetic mice develop mechanical hypo-, rather than hyperalgesia, i.e.…”

“…The paw withdrawal and tail-flick tests detecting the time to movement of a hindpaw or tail from a noxious heat source (Calcutt, 2002(Calcutt, , 2004 revealed hyperalgesia in STZ-diabetic and Zucker diabetic fatty rats with short-term diabetes Cameron et al, 2001a,b;Cotter et al, 2002;Ilnytska et al, 2006;Stevens et al, 2007), and hypoalgesia in STZ-diabetic and Zucker diabetic fatty rats with longer durations of diabetes Obrosova et al, in press), as well as STZ-diabetic , NOD , and leptin-deficient ob/ob mice (Drel et al, 2006a). Note that thermal hyperalgesia is sometimes observed in human subjects in the initial phase of diabetes mellitus (Dyck et al, 2000), whereas advanced clinical PDN is characterized by increased thermal perception thresholds (hypoalgesia) that progress to sensory loss, occurring in conjunction with degeneration of all types of peripheral nerve fibers (Calcutt, 2002(Calcutt, , 2004.…”

High-Fat Diet–Induced Neuropathy of Pre-Diabetes and Obesity

“…Evidence for the important role of PARP activation in pathological conditions associated with oxidative-nitrosative stress, i.e., diabetes complications, is emerging (43)(44)(45). We are the first to demonstrate the importance of this mechanism in diabetes-associated MNCV and SNCV deficits, neurovascular dysfunction, and sensory neuropathy (13,16,31). The present study suggests that PARP activation in both sciatic nerve and DRG neurons and glial cells is present at the stage of prediabetic neuropathy developing in the absence of overt hyperglycemia.…”

Characterization of the transcriptional machinery bound across the widely presumed type 2 diabetes causal variant, rs7903146, within TCF7L2

“…23 PARP-1 inhibitors have also been shown to alleviate symptoms of diabetic complications. [24][25][26] Furthermore, PARP-deficient mice are protected from streptozotocininduced diabetes. 27 With respect to the connection with oncology, missense mutations in TCF7L2 have been known for many years to be strongly linked with colorectal cancer risk.…”