Preventive effects of multisensory rehabilitation on development of cognitive dysfunction following systemic inflammation in aged rats.

Systemic inflammation can trigger transient or longer-lasting cognitive impairments, particularly in elderly patients. However, its pathogenesis has not been sufficiently clarified. In this study, we explored the potential effects of multisensory rehabilitation on cognitive dysfunction following systemic inflammation using an animal model. Aged male Wister rats were randomly injected intraperitoneally with either saline (control) or lipopolysaccharide (LPS; 5 mg/kg). After injection, both groups of rats were randomly assigned to either of two housing conditions (n = 8 in each condition): a standard cage environment (SC group) or a multisensory early rehabilitation environment (ER group). Cognitive function was examined after 7 days in the assigned environmental condition using a novel object recognition test. In the SC group, the LPS-treated rats showed impaired cognitive function compared with the control animals. These memory deficits were positively correlated with the levels of both tumor necrosis factor (TNF)-α and interleukin (IL)-1ß in the hippocampus. On the other hand, in the LPS-treated ER group, neither cognitive impairment nor an increase in hippocampal levels of both TNF-α and IL-1ß was found. These results imply that early rehabilitation (ER) intervention may be effective in preventing cognitive dysfunction following systemic inflammation via its anti-neuroinflammatory effects.

Effects of ketoprofen for prevention of postoperative cognitive dysfunction in aged rats.

Postoperative cognitive dysfunction is a common geriatric complication that may be associated with increased mortality. Here, we investigated the effects of postoperative analgesia with ketoprofen on cognitive functions in aged animals and compared its effectiveness to morphine. Rats were randomly allocated to one of four groups: isoflurane anesthesia without surgery (group C), isoflurane anesthesia with laparotomy (group IL), and isoflurane anesthesia with laparotomy plus postoperative analgesia with ketoprofen or morphine. There was no difference in postoperative locomotor activity among groups. In group IL, postoperative pain levels assessed by the Rat Grimace Scale significantly increased until 8 h after surgery, which was similarly inhibited by both ketoprofen and morphine. Cognitive function was assessed using radial arm maze testing for 12 consecutive days from postoperative day 3. Results showed that the number of memory errors in group IL were significantly higher than those in goup C. However, both ketoprofen and morphine could attenuate the increase in memory errors following surgery to a similar degree. Conversely, ketoprofen showed no effect on cognitive function in the nonsurgical rats that did not experience pain. Our findings suggest that postoperative analgesia with ketoprofen can prevent the development of surgery-associated memory deficits via its pain-relieving effects.

Reactive oxygen species-independent rapid initiation of mitochondrial apoptotic pathway by chelerythrine.

Chelerythrine, formerly identified as a protein kinase C inhibitor, has also been shown to inhibit the anti-apoptotic Bcl-2 family proteins. However, recent studies have now demonstrated that chelerythrine can induce the loss of mitochondrial membrane potential (ΔΨm), a membrane permeability transition (MPT), and the subsequent activation of the mitochondrial apoptotic pathway, even in the cells deficient in Bax and Bak. This suggests the existence of an alternative Bax/Bak-independent pathway for apoptosis. The generation of reactive oxygen species (ROS) from the mitochondrial electron transport chain (ETC) is also implicated in the cytotoxity elicited by chelerythrine. In our current study, we show that chelerythrine induces the rapid apoptotic death of H9c2 cardiomyocyte-derived cells within 8 min of treatment. The proteolytic activation of caspase9 and caspase3, crucial mediators of the mitochondrial apoptotic pathway, are also observed within 6 min of exposure to this drug. The generation of ROS is detected but at only marginal levels in the treated cells. The inhibition of the mitochondrial ETC by rotenone and malonate had almost no effects on ROS generation but in both cases effectively inhibited both cell death and the caspase activation induced by chelerythrine. Hence, chelerythrine initiates the rapid mitochondrial apoptotic death of H9c2 cardiomyoblastoma cells in a manner that is likely independent of the generation of ROS from mitochondria.