A.C. Kappelle

Cerebral function in diabetes mellitus

SummaryDiabetes mellitus is a common metabolic disorder associated with chronic complications such as nephropathy, angiopathy, retinopathy and peripheral neuropathy. Diabetes is not often considered to have deleterious effects on the brain. However, long-term diabetes results in a variety of subtle cerebral disorders, which occur more frequently than is commonly believed. Diabetic cerebral disorders have been demonstrated at a neurochemical, electrophysiological, structural and cognitive level; however, the pathogenesis is still not clear. Probably alterations in cerebral blood supply and metabolic derangements play a role, as they do in the pathogenesis of diabetic neuropathy. Furthermore, the brain is also affected by recurrent episodes of hypoglycaemia and poor metabolic control. We describe herein the cerebral manifestations of diabetes and discuss the putative pathogenetic mechanisms.

Potential use of glutathione for the prevention and treatment of diabetic neuropathy in the streptozotocin-induced diabetic rat.

SummaryIt has been shown that parameters of oxidative stress are increased in experimental diabetic neuropathy. The glutathione redox system is one of the intracellular scavenger systems for neutralizing free oxygen radicals. In this investigation we studied the effect of glutathione-treatment on the development of diabetic neuropathy in streptozotocin-induced diabetic rats by measuring sensory and motor nerve conduction velocities. The total study period was 10 weeks. Four groups of rats were studied: Group 1 consisted of non-diabetic, age-matched control rats; Group 2, of diabetic rats treated with placebo from week 0 to 10; Group 3, of diabetic rats treated with 200 mg glutathione/kg body weight i. v. two times per week from weeks 0 to 10; and Group 4, of diabetic rats treated with placebo from weeks 0 to 4 and as Group 3 from weeks 4 to 10. The sensory and motor nerve conduction velocity of rats treated prophylactically with glutathione (Group 3) were significantly different from those of rats treated with placebo (Group 2) or with glutathione administered at a later time point (Group 4). Complete restoration of sensory and motor nerve conduction velocity was not reached. There was a significant improvement in motor nerve conduction velocity from weeks 4 to 6 (p<0.005), but not in sensory nerve conduction velocity in the delayed treatment group (Group 4). In conclusion, treatment with glutathione, a free radical scavenger, is partially effective in the prevention of diabetic neuropathy in streptozotocin-induced diabetic rats, but is of limited value when the neuropathy is already present.

Beneficial effect of the Ca2+ antagonist, nimodipine, on existing diabetic neuropathy in the BB/Wor rat

1 Neuropathy is a frequently diagnosed complication of diabetes mellitus. Effective pharmacotherapy is not available. 2 The spontaneously diabetic BB/Wor rats develop secondary complications like neuropathy as do human diabetic patients. 3 BB/Wor rats treated with insulin via a subcutaneous implant show a significant impairment of sensory and motor nerve conduction velocity 6 weeks after the onset of diabetes mellitus. 4 Intraperitoneal treatment of diabetic BB/Wor rats with the Ca2+ antagonist, nimodipine (20 mg kg−1), from week 6 onwards every 48 h for a period of 6 weeks resulted in a significant increase of sensory and motor nerve conduction velocity. 5 Twelve weeks after the onset of diabetes mellitus BB/Wor rats show a 40% impairment of sciatic nerve blood flow as compared to the non‐diabetic age‐matched controls. Treatment with nimodipine (20 mg kg−1) from week 6 onwards significantly increased the sciatic nerve blood flow as compared to placebo‐treated diabetic BB/Wor rats. 6 The adrenergic responsiveness of the vasa nervorum of the sciatic nerve to tyramine and phenylephrine was investigated as a parameter for autonomic neuropathy. 7 The fact that nimodipine treatment restored the reduced response to tyramine independently of the reduced postsynaptic phenylephrine responsiveness indicates that nimodipine improves adrenergic responsiveness mainly at the presynaptic level.

Amelioration by the Ca2+ antagonist, nimodipine of an existing neuropathy in the streptozotocin‐induced, diabetic rat

1 Neuropathy is a frequently diagnosed complication in diabetic patients but an effective treatment does not exist. 2 The development of neuropathy in streptozotocin‐induced diabetic rats was monitored by measuring the motor and sensory nerve conduction velocity in the sciatic nerve. 3 A significant decrease in sensory and motor nerve conduction velocity was apparent in young, 14‐week‐old diabetic rats as compared to non‐diabetic, age‐matched controls 4 weeks after the induction of diabetes with streptozotocin. 4 Intraperitoneal treatment with the Ca2+ channel blocker, nimodipine, from week 4 onwards, in a dosage of 10 mg kg−1 or 20 mg kg−1 intraperitoneally per 48 h, resulted in a significant increase in sensory and motor nerve conduction velocity whereas treatment with 5 mg kg−1 intraperitoneally per 48 h was not effective. 5 One‐year‐old, adult, diabetic rats treated with nimodipine 20 mg kg−1 (treatment started again 4 weeks after induction of diabetes mellitus) also showed an increase of both sensory and motor nerve conduction velocity as compared to diabetic rats treated with placebo. 6 It is concluded that nimodipine ameliorates existing experimental diabetic neuropathy in streptozotocin‐induced diabetic rats in both young and adult animals.

Effects of nimodipine on sciatic nerve blood flow and vasa nervorum responsiveness in the diabetic rat

Evidence is accumulating that impairment of nerve blood flow is a key factor in the pathogenesis of diabetic neuropathy. Nimodipine, a 1,4-dihydropyridine type Ca2+ channel antagonist, has been shown to ameliorate an existing neuropathy in the streptozotocin-induced diabetic rat. In the present study the effect of diabetes mellitus itself and the effect of chronic nimodipine treatment on the sciatic nerve blood flow of streptozotocin-induced diabetic rats were investigated. Nerve blood flow was assessed using laser-Doppler flowmetry. Nerve blood flow gradually decreased during the first 10 weeks of diabetes mellitus and remained relatively stable thereafter. Intervention with nimodipine significantly improved the flow deficit observed in the diabetic rats. Vasa nervorum adrenergic responsiveness was also investigated. Diabetic rats showed a postsynaptic adrenergic hyporesponsiveness. Treatment with nimodipine restored the reduced presynaptic responsiveness independent of the postsynaptic adrenergic hyporesponsiveness. It was concluded that, in addition to direct neuroprotective effects, nimodipine exerts beneficial effects on disturbed nerve blood flow and on reduced presynaptic adrenergic responsiveness of the vasa nervorum in experimental diabetic neuropathy.

ACTH4–9 analogue ORG 2766 can improve existing neuropathy in streptozocin-induced diabetic rats

The effect of treatment of an existing neuropathy in streptozocin-induced diabetic rats with the ACTH4–9 analogue ORG 2766 was examined. Four groups of rats were studied: group 1 consisted of age-matched, non-diabetic controls and groups 2, 3 and 4 of diabetic rats. Sensory and motor nerve conduction velocity (SNCV and MNCV) were measured at weeks 0, 4, 6, 8 and 10. Four weeks after the administration of streptozocin (STZ) all diabetic rats showed a significant slowing of SNCV and MNCV. Treatment was then started: group 2 was treated with placebo, group 3 with a low dos (1 μg) of ACTH4–9 subcutaneously every 48h, and group 4 with a high dos (10 μg) of ACTH4–9 subcutaneously every 48 h. The animals treated with the high peptide dosage showed a significant improvement in both SNCV and MNCV from week 6 onwards, whereas this beneficial effect was not demonstrated for the rats treated with the low dosage. This study demonstrates that the ACTH4–9 analogue ORG 2766 can ameliorate existing diabetic neuropathy in STZ-induced diabetic rats.

Effect of exercise training on acute (crush lesion) and chronic (diabetes mellitus) peripheral neuropathy in the rat

The effect of moderate exercise training on acute and chronic neuropathy in two separate experiments was examined. Acute nerve dysfunction was induced by sciatic nerve crush lesion and chronic neuropathy by streptozotocin-induced diabetes mellitus (experimental diabetic neuropathy; EDN). Moderate exercise training was achieved by placing food and water, separately, at either end of a U-shaped tubular home cage (8 m). Recovery from the crush lesion and the development of EDN were monitored by evaluating the free walking pattern and nerve conduction velocity (NCV), respectively. In the acute neuropathy model, 24 days of exercise after the crush lesion resulted in an enhanced return of motor function in the early phase of recovery (P < 0.01) and an increased sensory NCV after 250 days in the late phase (P < 0.001). Diabetic rats benefited from this exercise training by showing fewer signs of EDN, as evidenced by a superior motor function (toespreading, calculated from the free walking pattern; P < 0.05) and an improvement in both motor and sensory NCV (both P < 0.05). We conclude that moderate exercise training is effective in enhancing recovery from acute peripheral neuropathy and in ameliorating the consequences of experimental chronic neuropathy in diabetic rats.

A disturbed macrocirculatory supply as a determinant for a reduced sciatic nerve blood flow in diabetic rats

The aim of this study was to evaluate macrocirculatory disturbances in relation to the reduced sciatic nerve blood flow seen in diabetic rats. Therefore, both femoral blood flow, the macrocirculatory arterial blood supply to the sciatic nerve, and the microcirculatory neuronal blood flow were measured. In order to differentiate between a direct vascular or a neuronal defect as a cause for the disturbed macrocirculatory blood flow the effects of the adrenocorticotropic hormone [ACTH]-(4-9) analogue, Org 2766, a neurotrophic compound without cardiovascular effects, were investigated on the femoral flow under basal as well as adrenergic-stimulated conditions. Adrenergic responsiveness to tyramine and phenylephrine effect on femoral flow was determined. Basal sciatic nerve and femoral blood flow were reduced by 48% and 42%, respectively, after 12 weeks of diabetes, without effect on blood pressure. Treatment with Org 2766, beginning 6 weeks after the induction of diabetes, had no influence on these basal haemodynamic variables. Femoral flow in diabetic rats showed a smaller response to tyramine and phenylephrine compared to the control. Org 2766 restored this disturbed flow response to that of the control rats. In conclusion, the decrease in basal femoral flow might be responsible for the lowered sciatic nerve blood flow. Although neuronal disturbances due to diabetes had a very minor role in the reduction of basal femoral blood flow the adrenergic-stimulated flow responsiveness was seriously affected in diabetic rats.

Influence of dihydropyridines on the recovery of sensory function after a caudal nerve crush in the rat

Nimodipine, a Ca2+ antagonist of the dihydropyridine type, is known to display a variety of neuropharmacological effects including facilitation of functional recovery following a crush of the sciatic nerve in the rat. In the present study, we investigated the effect of nimodipine, nifedipine (another Ca2+ antagonist with a lesser penetration in neural parenchyma) and Bay K 8644 (a Ca2+ agonist) treatment following a crush of the major caudal nerve. The caudal nerve crush model was used because this model provided the opportunity for longitudinal evaluation of nerve repair. Recovery of sensory function was tested by vocal reaction following local stimulation with a small electric current. The results suggest that nimodipine (20 mg/kg) both enhances the initial sprouting response and exerts an effect on the outgrowth rate of newly developed sprouts. Neither nifedipine (20 mg/kg) nor Bay K 8644 (0.5 mg/kg) had any influence on the recovery of nerve function. Furthermore, it was demonstrated that nimodipine, nifedipine and Bay K 8644 had no influence on nerve conduction velocity of the non-injured sciatic nerve indicating that there was no general beneficial effect of these agents on the peripheral nerve.