Protection of sensory function in diabetic rats by Neotrofin.

We investigated the ability of Neotrofin, an agent that enhances endogenous nerve growth factor (NGF) levels, to prevent phenotypic, functional and structural changes that occur in the peripheral nerve of streptozotocin-diabetic rats. Eight weeks of Neotrofin treatment prevented depletion of NGF protein in plantar foot skin and sciatic nerve of diabetic rats and increased NGF protein in associated skeletal muscles. These effects were accompanied by maintenance of normal nerve levels of the neuropeptides substance P and calcitonin gene related peptide. Thermal hypoalgesia and conduction slowing of large sensory fibres in diabetic rats were ameliorated by Neotrofin treatment, whereas there was no effect on conduction slowing in large motor fibres or on reduced myelinated fibre axonal calibre. Enhancing endogenous production of neurotrophic factors using small molecules may be an alternative to either exogenous treatment with neurotrophic factors or gene therapy as a therapeutic approach to treating diabetic neuropathy.

Neotrofin increases heme oxygenase-1 selectively in neurons.

There is evidence that heme oxygenase plays a role in cellular defense against reactive oxygen species and thereby has neuroprotective effects. We examined the interaction of Neotrofin, a cognitive-enhancing and neuroprotective drug, with the heme oxygenase system. In adult rats, both a single administration or seven daily injections of Neotrofin at 10, 30 or 100 mg/kg intraperitoneally increased HO-1 immunoreactivity in neurons of the hippocampal formation and its connections including CA1-4, fornix, septal nuclei, hippocampal commissure, septohippocampal nucleus, fimbria, anteroventral thalamic nucleus, frontal and parietal cortex. Prominent HO-1 staining of neuronal cells in the proximity of blood vessels and circumventricular organs was also observed. Increasing doses of Neotrofin resulted in an increase in the number of neuronal populations expressing HO-1 with 100 mg/kg evoking a widespread neuronal cell response in brain. Quantification by ELISA confirmed that intraperitoneal administration of 100 mg/kg Neotrofin caused a significant increase in HO-1 protein expression in the hippocampus. The increase was evident by 6 h post-injection, peaked at 24 h with a 4-fold increase, and persisted for at least 48 h. Similarly, oral administration of 100 mg/kg Neotrofin produced a 5-fold increase in HO-1 protein 24 h post-administration. The effect of Neotrofin on HO-1 appears to be at the transcriptional level, as suggested by an increase in HO-1 mRNA levels. Neotrofin treatment was also associated with a significant increase in HO-2 mRNA levels in whole brain homogenate. These data may explain the neuroprotective effects of Neotrofin in models of excitotoxic neuronal injury.