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Low-frequency whole-body vibration (WBV; 40 Hz), a low impact form of exercise, intervention for a month following moderate transient middle-cerebral artery occlusion (tMCAO) reduces infarct volume and improves motor function in reproductively senescent, middle-aged female rats. Since post-stroke cognitive decline remains a significant problem, the current study aims to investigate the efficacy of WBV in ameliorating post-tMCAO cognitive deficits and to determine the underlying putative mechanism(s) conferring benefits of WBV in middle-aged rats. Middle-aged rats of both sexes were randomly assigned to tMCAO (90 min) or sham surgery followed by exposure to either WBV (twice a day for 15 min each for 5 days a week over a month) or no WBV treatment groups. Following the last WBV treatment, rats were tested for hippocampus-dependent learning and memory using a water maze followed by harvesting brain and blood samples for histopathological and inflammatory marker analyses, respectively. Results show that post-tMCAO WBV significantly lessens cognitive deficits in rats of both sexes. Post-tMCAO WBV significantly decreased circulating pro-inflammatory cytokines and increased serum levels of irisin, a muscle-derived hormone that may play a role in brain metabolism and inflammation regulation, which suggests putative beneficial mechanisms of WBV.

Background: Stroke disproportionately kills more women than men and the risk of stroke remains high even at a young age among women smokers. Smoking prior to stroke is associated with increased post-stroke frailty. Frailty is characterized by an increased vulnerability to acute stressors and the reduced capacity of various bodily systems due to age-associated physiological deterioration. Such age related physiological deterioration of bone in laboratory animals and humans has shown to reverse after therapeutic intervention of whole body vibration (WBV). In the current study we aim to test the efficacy of WBV in reducing post-ischemic frailty and improving physical activity and cognition using a rat model of smoking attributed nicotine. Methods: Nicotine or saline exposed adult female rats underwent transient middle cerebral artery occlusion (tMCAO; 90 min) / sham-surgery and randomly assigned (n = 6-8 per group) to either WBV or control groups. Animals placed in the WBV (40 Hz) group underwent 30 days of WBV treatment performed twice daily for 15 min each session for 5 days each week. We monitored the frailty index (FI) prior to and 1 month after tMCAO alone or in combination with WBV. The FI was composed of the following criteria: 1) activity levels, 2) blood pressure (BP), 3) basic metabolic status, and 4) cognitive performance of rats. Animals were sacrificed on the 30th day of WBV treatment, and brain tissue was harvested for histopathological analysis. Results: Post-tMCAO WBV did not change activity levels or BP in nicotine or saline treated rats. Post-tMCAO WBV cognitive performance improved in saline group as compared to nicotine exposed rats. Sensorimotor function was also improved in tMCAO WBV saline group compared to nicotine-exposed rats. We observed 56% reduction in infarct volume of WBV treated rats as compared to control (p < 0.05). This difference was not seen in nicotine treated groups. Conclusions: The post-ischemic WBV intervention had no detrimental effects on the frailty parameters, decreased brain damage, and reduced frailty in control female rats, but not in the nicotine-exposed group. This suggests that WBV may be a potential therapy for non-smokers to reduce post-ischemic frailty and improve functional and cognitive outcomes after stroke.

Significance: Low frequency whole body vibration (LFV) at 40 Hz, a low impact form of exercise, for a month following mild transient middle-cerebral artery occlusion (tMCAO) reduces infarct volume and improves motor function in reproductively senescent, middle-aged female rats (1). In humans, LFV was shown to increase circulating levels of irisin, a skeletal muscle-derived hormone. Irisin has also been shown to play a crucial role in preserving mitochondrial function, preventing oxidative stress, and elevating expression of BDNF, among other neuroprotective measures. The current study aims to investigate the efficacy of LFV in ameliorating post-tMCAO cognitive deficits and to determine the putative role of irisin in conferring the benefits of LFV in middle-aged rats. Methods: Middle-aged rats of both sexes (5-8) were randomly assigned to tMCAO (90 min), or sham surgery followed by exposure to either LFV (twice a day for 15 min each for 5 days a week over a month) or no LFV treatment groups. Following the last LFV treatment, rats were tested for hippocampus-dependent learning and memory using a water maze followed harvesting brain and blood samples for histopathological and inflammatory marker analyses, respectively. In a parallel experiment in the absence of LFV, middle-aged female rats were randomly assigned to either saline or irisin treatment following tMCAO. Recombinant irisin was purchased from PeproTech (Rocky Hill, NJ). Rats were treated with irisin (0.2 μg/g BW; IP) or saline for a month followed by their brains were assessed by histopathology. Results: Post-tMCAO LFV significantly lessens cognitive deficits in rats of both sexes. It also significantly decreased circulating pro-inflammatory cytokines and increased serum levels of native irisin. Quantification of infarct volume irisin-treated rats demonstrated that, compared to saline, infarct volume was significantly reduced. Saline treatment resulted in 234 ± 30 mm 3 , while irisin treatment yielded 128 ± 34 mm 3 (p<0.05) of infarct volume. Conclusion: Irisin, either as elicited by LFV or administered exogenously without LFV, regulates brain metabolism and inflammation and its beneficial effects can be stimulated by LFV.Reference: 1. Raval, A.P., et al., Int J Mol Sci, 2018. 19 (9).