Prevention of sensory disorders in diabetic Sprague-Dawley rats by aldose reductase inhibition or treatment with ciliary neurotrophic factor

Abstract

Aims/hypothesis. Sensory neuropathy in diabetic patients frequently presents itself as progressive loss of thermal perception, while some patients describe concurrent spontaneous pain, allodynia or hyperalgesia. Diabetic rats develop thermal hypoalgesia and tactile allodynia by unknown mechanisms. We investigated whether sensory disorders in rats were related to glucose metabolism by aldose reductase. We also explored the therapeutic potential of exogenous neurotrophic factors. Methods. Behavioural assessments of thermal and tactile sensitivity were performed in normal rats and in rats with streptozotocin-induced diabetes. Some of the rats were treated with insulin, aldose reductase inhibitors, ciliary neurotrophic factor or brain-derived neurotrophic factor. Results. Thermal hypoalgesia was present after 8 weeks of diabetes and was prevented by insulin treatment, which maintained normoglycaemia, by the aldose reductase inhibitor Statil or by ciliary neurotrophic factor. Brain-derived neurotrophic factor did not have an effect. When diabetic rats were tested after shorter durations of diabetes, they showed transient thermal hyperalgesia after 4 weeks which progressed to thermal hypoalgesia after 8 weeks. The aldose reductase inhibitor IDD 676 (Lidorestat), given from the onset of diabetes, prevented the development of thermal hyperalgesia and also stopped progression to thermal hypoalgesia when delivered in the last 4 weeks of an 8-week period of diabetes. Tactile allodynia was not prevented by neurotrophic factor or aldose reductase inhibitor treatment. Conclusions/interpretation. Transient thermal hyperalgesia and subsequent progressive thermal hypoalgesia occur in diabetic rats secondary to exaggerated flux through the polyol pathway. A depletion of ciliary neurotrophic factor mediated by the polyol pathway may be involved in the aetiology of thermal hypoalgesia.

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

“…Here, the tail-flick response latency appeared decreased in rats with short-term STZ-induced diabetes, consistent with independent measurements of the paw-withdrawal time from noxious thermal stimuli, which, in contrast to the tail-flick test, included supraspinal sensory processing (23). Diabetic rats demonstrated reduced latencies of both responses, which is consistent with the presence of transient thermal hyperalgesia and is in line with our previous studies (13,30) and other reports (3,7,9). Both tail-flick and paw-withdrawal latencies were at least partially corrected by PARP inhibition, consistent with other findings (3,4,7) implicating oxidative-nitrosative stress as well as other mechanisms contributing to free radical and oxidant generation (e.g., increased aldose reductase [9] and protein kinase C [26] activities) to abnormal sensory responses to thermal noxious stimuli in diabetes.…”

“…Similar phenomenon is observed in diabetic rats where the light touch (Ͻ15 g) of von Frey filaments or light stroking of the paw induces a withdrawal response from the stimulus (9,23,25). The mechanisms of tactile allodynia are not studied in detail.…”

“…Despite these limitations, assessment of behavioral responses to external stimuli in diabetic rodents provides valuable information regarding the mechanisms of abnormal sensation and pain associated with diabetes. Recent behavioral studies have demonstrated that 1) both diabetic rats and mice display altered thermal and mechanical algesia in response to noxious stimuli as well as tactile allodynia, although a type of response (i.e., hyper-or hypoalgesia) often depends on animal species and duration of diabetes (3,4,9,13) and 2) abnormal sensory responses are alleviated by protracted normoglycemia (23) and are amenable to at least some pathogenetic treatments (e.g., aldose reductase inhibitors [9], neurotrophic factors [9], the protein kinase C inhibitor LY333531 [26], rosuvastatin [27], and antioxidants [3,4,7,13]) that also reduce manifestations of large motor and sensory fiber neuropathy (1-5,26 -28). Our findings have shown that 1) PARP activation is implicated in hyperalgesia to noxious thermal, mechanical, and chemical stimuli and 2) PARP inhibitor treatment alleviates, but does not completely normalize, tail-flick and paw-withdrawal response latencies, mechanical and tactile withdrawal thresholds, and exaggerated flinching behavior in rats with short-term STZ-induced diabetes.…”

Aldose Reductase Pathway Inhibition Improved Vascular and C-Fiber Functions, Allowing for Pressure-Induced Vasodilation Restoration During Severe Diabetic Neuropathy

“…Our study showed that glucose metabolism by aldose reductase contributed to the etiology of thermal hypoalgesia, and aldose reductase inhibition also normalized thermal responses. This is concordant with Calcutt et al (38), who showed the efficiency of ARI to prevent thermal hypoalgesia in 8-week diabetic rats. Thus, we suggest that restoration of normal algesia in sorbinil-treated diabetic mice is caused by recovery of C-fiber terminals, allowing for pressure-induced vasodilation restoration.…”

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

“…Numerous pharmacological studies in animal models have been performed to sort out the involvement of the key hyperglycemia-induced biochemical mechanisms in diabetesassociated changes in thermal nociception. Aldose reductase inhibitors (ARIs, Calcutt et al, 2004), antioxidants i.e., taurine (Li et al, 2005b), α-lipoic acid (Cameron et al, 2001a), the hydroxyl radical scavenger dimethylthiourea (Cameron et al, 2001b), as well as the protein kinase C inhibitor LY333531 (Cotter et al, 2002), the PARP inhibitor 1,5-isoqunolinediol and PARP inhibitor-containing combination therapies (Li et al, 2005a), have been found to prevent or correct thermal hyperalgesia in STZ-diabetic rats. Taurine prevented thermal hyperalgesia in ZDF rats (Li et al, 2006).…”