Ex vivo adenoviral vector-mediated neurotrophin gene transfer to olfactory ensheathing glia: Effects on rubrospinal tract regeneration, lesion size, and functional recovery after implantation in the injured rat spinal cord

The present study uniquely combines olfactory ensheathing glia (OEG) implantation with ex vivo adenoviral (AdV) vector-based neurotrophin gene therapy in an attempt to enhance regeneration after cervical spinal cord injury. Primary OEG were transduced with AdV vectors encoding rat brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), or bacterial marker protein -galactosidase (LacZ) and subsequently implanted into adult Fischer rats directly after unilateral transection of the dorsolateral funiculus. Implanted animals received a total of 2 x 105 OEG that were subjected to transduction with neurotrophin-encoding AdV vector, AdV-LacZ, or no vector, respectively. At 4 months after injury, lesion volumes were smaller in all OEG implanted rats and significantly reduced in size after implantation of neurotrophin-encoding AdV vector-transduced OEG. All OEG grafts were filled with neurofilament-positive axons, and AdV vector-mediated expression of BDNF by implanted cells significantly enhanced regenerative sprouting of the rubrospinal tract. Behavioral analysis revealed that OEG-implanted rats displayed better locomotion during horizontal rope walking than unimplanted lesioned controls. Recovery of hind limb function was also improved after implantation of OEG that were transduced with a BDNF- or NT-3-encoding AdV vector. Hind limb performance during horizontal rope locomotion did directly correlate with lesion size, suggesting that neuroprotective effects of OEG implants contributed to the level of functional recovery. Thus, our results demonstrate that genetic engineering of OEG not only resulted in a cell that was more effective in promoting axonal outgrowth but could also lead to enhanced recovery after injury, possibly by sparing of spinal tissue

rhGGF2 protects against cisplatin-induced neuropathy in the rat

In many patients treated with cisplatin a peripheral sensory neuropathy develops. This side-effect is considered dose-limiting, and therefore restricts the total dose of cisplatin that can be administered. Recent in vitro and in vivo studies suggest that recombinant human Glial Growth Factor 2 (rhGGF2) has neuroprotective effects. This prompted us to investigate in a rat model whether rhGGF2 ameliorates cisplatin neuropathy. A total of 48 rats were randomly divided into four groups of 12 rats each. Three groups received cisplatin and were treated with either 0.1 mg/kg rhGGF2, 0.3 mg/kg rhGGF2 or placebo. The fourth group (saline/placebo) served as age-matched controls. In the cisplatin/placebo treated rats a neuropathy developed, as determined by measurements of the nerve conduction velocity (NCV). Treatment with rhGGF2 dose-dependently protected against the neuropathy. Histological examination and morphometric analysis revealed that rhGGF2 also protects against cisplatin-induced changes in the morphology and size of DRG satellite cell nuclei. In a control study rhGGF2 did not affect normal NCV development. We conclude that rhGGF2 treatment is of benefit in the treatment of cisplatin neuropathy in the ra

Neuronal Ca2+ disregulation in diabetes mellitus

The Ca2+ hypothesis of brain ageing and dementia may account for part of the available data on the pathogenesis of dementia and certain neurodegenerative disorders. The hypothesis proposes that disturbances in the homeostasis of neuronal cytosolic free Ca2+ are part of a final common pathway, ultimately leading to neuronal dysfunction and cell death. The hypothesis also proposes that a small change in cytosolic free Ca2+ sustained over a long period of time will result in similar damage as a large change over a short period. Diabetes mellitus is associated with neurological complications in the peripheral and central nervous system, as reflected in peripheral neuropathy, modest cognitive impairments and an increased risk of dementia. In animal models of diabetes, learning impairments are associated with alterations in Ca2+ -dependent forms of hippocampal synaptic plasticity. Disturbances in the homeostasis of cytosolic free Ca2+ may present a final common pathway in the multifactorial pathogenesis of neurological complications of diabetes, which involves vascular changes, oxidative stress, and non-enzymatic protein glycation. In line with the Ca2+ hypothesis of neurodegenerative disorders, a prolonged, small increase in basal cytosolic Ca2+ levels indeed exists in sensory neurones of diabetic animals. In addition, Ca2+ dynamics are affected. Ca2+ channel blockers, such as nimodipine, have been shown to improve experimental peripheral neuropathy, through a vascular mechanism, possibly in combination with direct neuronal effects. Preliminary studies indicate that nimodipine may also improve Ca2+-dependent forms of synaptic plasticity in the hippocampus of diabetic rats

Combined treatment with αMSH and methylprednisolone fails to improve functional recovery after spinal injury in the rat

To date, relatively little progress has been made in the treatment of spinal cord injury (SCI)-related neurological impairments. Until now, methylprednisolone (MP) is the only agent with clinically proven beneficial effect on functional outcome after SCI. Although the mechanism of action is not completely clear, experimental data point to protection against membrane peroxidation and edema reduction. The melanocortin melanotropin is known to improve axonal regeneration following sciatic nerve injury, and to stimulate corticospinal outgrowth after partial spinal cord transection. Recently, we showed that intrathecally administered MSH had beneficial effects on functional recovery after experimental SCI. Since both drugs have shown their value in intervention studies after (experimental) spinal cord injury (ESCI), we decided to study the effects of combined treatment. Our results again showed that αMSH enhances functional recovery after ESCI in the rat and that MP, although not affecting functional recovery adversely by itself, abolished the effects observed with αMSH when combined. Our data, thus, suggest that the mechanism of action of MP interferes with that of αMSH