Selective vulnerability of brain regions to oxidative stress in a non-coma model of insulin-induced hypoglycemia.

Insulin-induced hypoglycemia causes the death of neurons in particular brain regions including the cerebral cortex, the striatum and the hippocampus, while the cerebellum and the brain stem are more resistant. The mechanisms underlying this selective vulnerability to hypoglycemic damage are unknown. In the present study we have analyzed the presence of lipoperoxidation products and nitrosilated protein residues in different rat brain regions during and after the induction of hypoglycemia. Insulin-injected hypoglycemic rats were sacrificed before the onset of the isoelectric period or infused with glucose to end hypoglycemia, and then sacrificed at different times. Increased lipoperoxidation levels were observed before the onset of the isoelectric period, while 3-nitrotyrosine (NT) residues in proteins and NT-positive cells were only observed after glucose reperfusion. These changes were found only in vulnerable brain regions, while none of them was evident in the cerebellum, suggesting a correlation between oxidative damage and vulnerability to hypoglycemic neuronal death in selective brain regions. Results suggest that a pro-oxidant state is promoted in certain brain regions during hypoglycemia and after the glucose reperfusion phase, which might result from the activation of several oxidative stress pathways and may be related to subsequent cell death.

CpG-containing ODN has a limited role in the protection against Toxoplasma gondii.

Bacterial DNA containing immunostimulatory motifs (CpG) induces the development of a T(H1) immune response. Since protection against Toxoplasma gondii is correlated with this type of response, the aim of this work was to determine if a synthetic oligodeoxynucleotide (ODN) containing CpG sequences could be useful as adjuvant for the induction of a long-lasting protective immune response against T. gondii. BALB/c mice immunized with a total soluble antigen of T. gondii (TSA2) mixed with ODN-containing CpG sequences developed a typical TH1 response, as determined by antibody isotypes and interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) production by spleen cells. However, they did not resist a challenge with the virulent RH strain of the parasite. Absence of protection paralleled with lower levels of IFN-gamma, when compared with mice vaccinated with the live tachyzoites of the attenuated ts.4 strain of the parasite, which resisted this challenge. Intraperitoneal injection of ODN alone to mice induced a high degree of resistance to a lethal challenge inoculated by the same route. Nevertheless, this nonspecific protection was transient. Thus, the use of ODN containing CpG motifs as adjuvant is of limited value for the induction of a protective immune response against T. gondii.

Acetoacetate protects hippocampal neurons against glutamate-mediated neuronal damage during glycolysis inhibition.

Glucose is the main substrate that fulfills energy brain demands. However, in some circumstances, such as diabetes, starvation, during the suckling period and the ketogenic diet, brain uses the ketone bodies, acetoacetate and beta-hydroxybutyrate, as energy sources. Ketone body utilization in brain depends directly on its blood concentration, which is normally very low, but increases substantially during the conditions mentioned above. Glutamate neurotoxicity has been implicated in neurodegeneration associated with brain ischemia, hypoglycemia and cerebral trauma, conditions related to energy failure, and to elevation of glutamate extracellular levels in brain. In recent years substantial evidence favoring a close relation between glutamate neurotoxic potentiality and cellular energy levels, has been compiled. We have previously demonstrated that accumulation of extracellular glutamate after inhibition of its transporters, induces neuronal death in vivo during energy impairment induced by glycolysis inhibition. In the present study we have assessed the protective potentiality of the ketone body, acetoacetate, against glutamate-mediated neuronal damage in the hippocampus of rats chronically treated with the glycolysis inhibitor, iodoacetate, and in hippocampal cultured neurons exposed to a toxic concentration of iodoacetate. Results show that acetoacetate efficiently protects against glutamate neurotoxicity both in vivo and in vitro probably by a mechanism involving its role as an energy substrate.