SummaryObesity and hyperinsulinemia are risk factors for stroke. We tested the hypothesis that caloric restriction, which reduces the incidence of age‐related obesity and metabolic syndrome, may represent an efficient and cost‐effective strategy for preventing stroke and its devastating consequences. To this end, we placed aged, obese Sprague‐Dawley aged rats on a calorie‐restricted diet for 8 weeks prior to the experimental infarction. Stroke in this animal model caused a progressive decrease in weight that reached a minimum at day 6 for the young rats, and at day 10 for the aged, ad libitum‐fed rats. However, in aged animals that were calorie‐restricted prior to stroke, body weight did not decrease after stroke, but we noted accelerated body weight gain shortly thereafter starting at day 5 poststroke. Moreover, calorie‐restricted aged animals showed improved behavioral recovery in tasks requiring complex sensorimotor skills, or in tasks requiring cutaneous sensitivity and sensorimotor integration or spatial memory. Likewise, calorie‐restricted aged rats showed significant poststroke increases in serum glucose, insulin, and IGF1 levels, as well as CR‐specific changes in the expression of gene transcripts involved in glycogen metabolism, IGF signaling, apoptosis, arteriogenesis, and hypoxia. In conclusion, our study shows that recovery from stroke is enhanced in aged rats by a dietary regimen that reduces body weight prior to infarct.

Worldwide, millions of individuals suffer an ischemic stroke each year, causing major disability, especially in the elderly, where stroke is the number one cause of disability. However, to date, no effective therapy exists that targets the functional recovery after stroke. After necrosis, neuroinflammation is a common feature of the acute stroke and a major obstacle to tissue restoration. In the lesioned area, the dying neurons release chemotactic signals, such as fractalkine/CX3CL1, which evoke “eat-me” signals that are recognized by microglia expressing complement C3a receptor (C3aR), resulting in phagocytosis of the dying but still viable neurons, known as secondary phagocytosis. Using a mouse model of stroke and two-photon microscopy, we aimed to attenuate poststroke phagocytosis of the dying but still viable neurons by using SB 290157, an antagonist of C3aR. We found that intracortical administration of SB 290157 reduced the number of inflammatory microglial cells expressing ED1 and Iba1 antigens at the lesion site. We could show, in vivo, that two days after a needle-induced cortical lesion there were less microglial cells present around the injury site, displaying less high-order branches and an increase in the lower order ones, suggesting an attenuated phagocytic phenotype in treated animals as compared with controls. We conclude that the C3aR antagonist, SB 290157, may be used in the future to limit the neuronal death by limiting secondary phagocytosis after stroke.

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Suicide is one of the leading causes of death globally for all ages, and as such presents a very serious problem for clinicians worldwide. However, the underlying neurobiological pathology remains to a large extent unknown. In order to address this gap, we have carried out a genome-wide investigation of the gene expression in the amygdala, hippocampus, prefrontal cortex and thalamus in post-mortem brain samples obtained from 20 suicide completers and 7 control subjects. By KEGG enrichment analysis indicated we identified novel clusters of downregulated pathways involved in antigen neutralization and autoimmune thyroid disease (amygdala, thalamus), decreased axonal plasticity in the hippocampus. Two upregulated pathways were involved in neuronal death in the hippocampus and olfactory transduction in the thalamus and the prefrontal cortex. Autoimmune thyroid disease pathway was downregulated only in females. Metabolic pathways involved in Notch signaling amino acid metabolism and unsaturated lipid synthesis were thalamus-specific. Suicide-associated changes in the expression of several genes and pseudogenes that point to various functional mechanisms possibly implicated in the pathology of suicide. Two genes (SNORA13 and RNU4-2) involved in RNA processing were common to all brain regions analyzed. Most of the identified gene expression changes were related to region-specific dysregulated manifestation of genetic and epigenetic mechanisms underlying neurodevelopmental disorders (SNORD114-10, SUSd1), motivation, addiction and motor disorders (CHRNA6), long-term depression (RAB3B), stress response, major depression and schizophrenia (GFAP), signal transduction at the neurovascular unit (NEXN) and inhibitory neurotransmission in spatial learning, neural plasticity (CALB2; CLIC6, ENPP1). Some of the differentially expressed genes were brain specific non-coding RNAs involved in the regulation of translation (SNORA13). One, (PARM1) is a potential oncogene and prognostic biomarker for colorectal cancer with no known function in the brain. Disturbed gene expression involved in antigen neutralization, autoimmunity, neural plasticity, stress response, signal transduction at the neurovascular unit, dysregulated nuclear RNA processing and translation and epigenetic imprinting signatures is associated with suicide and point to regulatory non-coding RNAs as potential targets of new drugs development.

After cerebral ischemia, the ratio between astroglial cells and neurons in the neurovascular unit is disrupted in the perilesional area. We hypothesized that restoring the balance within the neurovascular unit may lead to an improved neurorestoration after focal ischemia. Recently, an innovative technology has been invented to efficiently convert proliferating astroglial cells into neurons in the injured young brain. However, the conversion efficacy of this technology has not been explored in the post-stroke brains of the aged rodents. To this end, we used a retroviral delivery system encoding the transcription factor Ngn2 alone or in combination with the antiapoptotic factor Bcl-2 to target proliferating astrocytes in the neocortex of young and aged mice after cerebral ischemia. Successful direct in vivo reprogramming of reactive glia into neuroblasts and mature neurons was assessed by cellular phenotyping. We found that the conversion efficacy of proliferating astrocytes into neurons after cerebral ischemia in young and aged mice is disappointingly low, most likely because the therapeutic vectors carrying the conversion gene are engulfed by phagocytes shortly after intracortical administration. We conclude that other viral vectors and combinations of transcription factors should be employed to improve the efficacy of glia-to-neuron conversion after stroke in young and aged rodents.