Abstract
Diabetic neuropathy is common and disabling despite glycemic control. Novel neuroprotective approaches are needed. Thrombin and hypercoagulability are associated with diabetes and nerve conduction dysfunction. Our aim was to study the role of thrombin in diabetic neuropathy. We measured thrombin activity by a biochemical assay in streptozotocin (STZ)-induced diabetic neuropathy in male Sprague-Dawley rats. Neuropathy severity was assessed by thermal latency and nerve conduction measures. Thermal latencies were longer in diabetic rats, and improved with the non-specific serine-protease inhibitor Tosyl-L-lysine-chloromethyl ketone (TLCK) treatment (p<0.01). The tail nerve of diabetic rats showed slow conduction velocity (p˂0.01), and interestingly, increased thrombin activity was noted in the sciatic nerve (p˂0.001). Sciatic nodes of Ranvier and the thrombin receptor, protease activated receptor 1 (PAR1) reactivity showed abnormal morphology in diabetic animals by immunofluorescence staining (p<0.0001). Treatment of diabetic animals with either the specific thrombin inhibitor, N-alpha 2 naphtalenesulfonylglycyl alpha-4 amidino-phenylalaninepiperidide (NAPAP) or TLCK preserved normal conduction velocity, (p˂0.01 and p = 0.01 respectively), and prevented disruption of morphology (p˂0.05 and p˂0.03). The results establish for the first time an association between diabetic neuropathy and excessive activation of the thrombin pathway. Treatment of diabetic animals with thrombin inhibitors ameliorates both biochemical, structural and electrophysiological deficits. The thrombin pathway inhibition may be a novel neuroprotective therapeutic target in the diabetic neuropathy pathology.
Highlights
Diabetes mellitus (DM) is a common health problem in the western world [1] and diabetic peripheral neuropathy (DPN) affects 60% of all DM patients [2]
Thrombin pathway is activated by a number of G-protein coupled protease activated receptors (PARs), including protease activated receptor 1 (PAR1), which is present on glia and neurons [6]
Thrombin activity levels were standardized according to control group which included control rats treated with saline, naphtalenesulfonylglycyl alpha-4 amidino-phenylalaninepiperidide (NAPAP) and Tosyl-Llysine-chloromethyl ketone (TLCK)
Summary
Diabetes mellitus (DM) is a common health problem in the western world [1] and diabetic peripheral neuropathy (DPN) affects 60% of all DM patients [2]. Thrombin is key coagulation factor and is known to participate in other cellular processes including inflammation [4], and neuronal degeneration [5]. In the peripheral nervous system (PNS) thrombin was previously shown to act in neurogenic inflammation, pain, motor function and nerve injuries [7]. We have previously demonstrated that thrombin pathway activation in the peripheral nerve induces a conduction block at the node of Ranvier. This implies a possible thrombin pathway involvement in peripheral nerve disease such as diabetic neuropathy. Platelet aggregation was reported to be higher in patients with diabetic neuropathy. These patients showed capillary pathology as well. Involvement of coagulation abnormalities in the pathogenesis of diabetic neuropathy was suggested before [9]
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