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.

Despite the fact that a high proportion of elderly stroke patients develop mood disorders, the mechanisms underlying late-onset neuropsychiatric and neurocognitive symptoms have so far received little attention in the field of neurobiology. In rodents, aged animals display depressive symptoms following stroke, whereas young animals recover fairly well. This finding has prompted us to investigate the expression of serotonin receptors 2A and 2B, which are directly linked to depression, in the brains of aged and young rats following stroke. Although the development of the infarct was more rapid in aged rats in the first 3 days after stroke, by day 14 the cortical infarcts were similar in size in both age groups i.e. 45% of total cortical volume in young rats and 55.7% in aged rats. We also found that the expression of serotonin receptor type B mRNA was markedly increased in the perilesional area of aged rats as compared to the younger counterparts. Furthermore, histologically, HTR2B protein expression in degenerating neurons was closely associated with activated microglia both in aged rats and human subjects. Treatment with fluoxetine attenuated the expression of Htr2B mRNA, stimulated post-stroke neurogenesis in the subventricular zone and was associated with an improved anhedonic behavior and an increased activity in the forced swim test in aged animals. We hypothesize that HTR2B expression in the infarcted territory may render degenerating neurons susceptible to attack by activated microglia and thus aggravate the consequences of stroke.

Ischemic stroke swiftly induces a wide spectrum of pathophysiological sequelae, particularly in the aged brain. The translational failure of experimental therapies, might partially be related to monotherapeutic approaches, not address potential counter-mechanisms sufficiently or within the best time window. For example, therapeutic effects relying on stem/progenitor cell mobilization by granulocyte-colony stimulating factor (G-CSF), require approximately a week to become manifest, which is potentially beyond the optimal timing. Here, We tested the hypothesis that treating post-stroke aged rats with the combination of bone marrow-derived mononuclear cells (BM MNC) and G-CSF improves the long term (56 days) functional outcome by compensating the delay before G-CSF effects come to full effect. 1x10(6) syngeneic BM MNC per kg bodyweight (BW) with G-CSF (50 µg/kg, given intraperitoneal by via the jugular vein to aged Sprague- Dawley rats, six hours post-stroke. This process was repeated daily, for a 28 day period. Infarct volume was measured by magnetic resonance imaging at 3 and 48 days post-stroke and additionally by immunohistochemistry at day 56. Functional recovery was tested during the entire post-stroke survival period. Daily G-CSF treatment led to a robust and consistent improvement of neurological function, but did not alter final infarct volumes. The combination of G-CSF and BM MNC, did not further improve post-stroke recovery. The lack of an additional benefit may be due to interaction between both approaches, and to a lesser extent, in the insensitivity of the aged brains' regenerative mechanisms. Also considering recent findings on other tandem approaches involving G-CSF in animal models featuring relevant co-morbidities, we conclude that such combination therapies are not the optimal approach to treat the acutely injured aged brain.

Long-term hypothermia may be a viable clinical approach by simultaneously targeting multiple processes including better tissue preservation, enhanced vascular density and improved behavioral performance.