Degeneration of peripheral nervous system in rats experimentally induced by methylmercury intoxication.

The objective of this study is to elucidate the primary action of methylmercury chloride (MMC) intoxication on peripheral nervous system. We chronologically observed the pathological changes of sciatic nerve, dorsal root ganglion (DRG) neurons, ventral and dorsal roots in rats given 4 mg/kg/day of MMC on consecutive days and killed on days 11, 15, 18 and 21. On day 11, an initial axonal degeneration of type B neuron occurred, predominantly in the distal portions of sciatic nerve. The DRG type A neuron was infiltrated by MRF-1-positive macrophages on day 11. Electron microscopy also demonstrated degenerated mitochondria in type A neuron. On day 21, most of type A neurons seemed to have disappeared. However, type B neurons were well preserved. Immunoblotting with monoclonal antibodies, P0 and neurofilament, demonstrated that both of proteins significantly decreases from day 15. In conclusion, these results indicate that the primary action on type A neuron is the neuron body that consequently results in an anterograde degeneration of nerve fibers, while the type B neuron degeneration occurs in a dying-back process in this subacute model. These findings suggest that the mechanisms involved in the degeneration induced by MMC vary and may depend on certain intrinsic factors peculiar to these neurons.

Vascular endothelial growth factor improves the cognitive decline of Alzheimer's disease via concurrently inducing the expression of ADAM10 and reducing the expression of ß-site APP cleaving enzyme 1 in Tg2576 mice.

Alzheimer's disease (AD) is primarily characterized by the production and deposit of ß-amyloid protein (Aß) in ß-amyloid plaques (APs). On this basis, we investigated whether vascular endothelial growth factor (VEGF), a growth factor with important neuroprotective activity, may provide a therapeutic opportunity for treating AD. We initially found that the expression and production of VEGF was downregulated in the brains of Tg2576 mice during the course of AD development and progression. Restoring VEGF in the brains of Tg2576 mice antagonized the production and deposit of Aß in Tg2576 mice. The addition of VEGF concurrently increased the expression of disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) and decreased the expression of ß-site APP cleaving enzyme 1 (BACE1), which contributes to the enhanced clearance of Aß in vivo. By decreasing the production and deposit of Aß, VEGF improved the cognitive decline of Tg2576 mice. These observations provide a novel implication for VEGF as a therapeutic approach for the treatment of AD.

Altered Plasticity of Glycogen Phosphorylase in Forebrain Gliosomes Obtained from Insulinoma Patients.

We investigated a control model of hypoglycemia-exposed brain tissues from a small series of patients with insulinoma, immediately dissect them, and perform a differential cold centrifugation to obtain gliosomes and examine alterations of glycogenolytic mechanisms. The BB as well as MM isoforms of glycogen phosphorylase enzymatic protein expression remained unaltered between insulinoma and control subjects within the gliosomes. However, the glycogen phosphorylase remained in a form that was potentially activated several folds on placing the gliosomes in a glucose-free medium. This was examined by its increased interaction with protein kinase A. Inhibitors of glycogen phosphorylase was used as controls. Furthermore, we demonstrated that glucose-depleted medium enhanced production of both ATP and lactate by the gliosomes. It is possible that a portion of glucose obtained from glycogen breakdown was circuited through glycolytic pathways to generate ATP. It has been reported earlier that ATP within gliosomes plays a major role in glutamate uptake, thus potentially preventing seizure during active bouts of hypoglycemia. Lactate shuttle from astrocytes is a potential mechanism to balance neuronal bioenergetics during events of hypoglycemia. Newer approaches to pharmacologically modulate glycogen phosphorylase may prove to be rational approach for neuroprotective therapy in this common clinical syndrome of hypoglycemia.