Postoperative cognitive dysfunction, POCD, afflicts a large number of elderly surgical patients following surgery with general anesthesia. Mechanisms of POCD remain unclear. N-methyl-D-aspartate (NMDA) receptors, critical in learning and memory, that display protein expression changes with age are modulated by inhalation anesthetics. The aim of this study was to identify protein expression changes in NMDA receptor subunits and downstream signaling pathways in aged rats that demonstrated anesthesia-induced spatial learning impairments. Three-month-old and 18-month-old male Fischer 344 rats were randomly assigned to receive 1.8% isoflurane/70 % nitrous oxide (N2O) anesthesia for 4h or no anesthesia. Spatial learning was assessed at 2 weeks and 3 months post-anesthesia in Morris water maze. Hippocampal and cortical protein lysates of 18-month-old rats were immunoblotted for activated caspase 3, NMDA receptor subunits, and extracellular-signal regulated kinase (ERK) 1/2. In a separate experiment, Ro 25-6981 (0.5mg/kg dose) was administered by I.P. injection before anesthesia to 18-month-old rats. Immunoblotting of NR2B was performed on hippocampal protein lysates. At 3 months post-anesthesia, rats treated with anesthesia at 18-months-old demonstrated spatial learning impairment corresponding to acute and long-term increases in NR2B protein expression and a reduction in phospho-ERK1/2 in the hippocampus and cortex. Ro 25-6981 pretreatment attenuated the increase in acute NR2B protein expression. Our findings suggest a role for disruption of NMDA receptor mediated signaling pathways in the hippocampus and cortex of rats treated with isoflurane/ N2O anesthesia at 18-months-old, leading to spatial learning deficits in these animals. A potential therapeutic intervention for anesthesia associated cognitive deficits is discussed.

Although chronic 17β-estradiol (E2) has been shown to be a cognition-preserving and neuroprotective agent in animal brain injury models, concern regarding its safety was raised by the failed translation of this phenomenon to the clinic. Previously, we demonstrated that a single bolus of E2 48 hr prior to ischemia protected the hippocampus from damage in ovariectomized rats via phosphorylation of cyclic-AMP response element binding protein, which requires activation of estrogen receptor subtype beta (ER-β). The current study tests the hypothesis that long-term periodic E2-treatment improves cognition and reduces post-ischemic hippocampal injury by means of ER-β activation. Ovariectomized rats were given ten injections of E2 at 48 hr intervals for 21 days. Hippocampal-dependent learning, memory and ischemic neuronal loss were monitored. Results demonstrated that periodic E2 treatments improved spatial learning, memory and ischemic neuronal survival in ovariectomized rats. Additionally, periodic ER-β agonist treatments every 48 hr improved post-ischemic cognition. Silencing of hippocampal ER-β attenuated E2-mediated ischemic protection suggesting that ER-β plays a key role in mediating the beneficial effects of periodic E2 treatments. This study emphasizes the need to investigate a periodic estrogen replacement regimen to reduce cognitive decline and cerebral ischemia incidents/impact in post-menopausal women.

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.