Evidence that microglia mediate the neurobiological effects of chronic psychological stress on the medial prefrontal cortex.

Psychological stress contributes to the development of clinical depression. This has prompted many preclinical studies to investigate the neurobiology of this relationship, however, the effects of stress on glia remain unclear. In this study, we wished to determine, first, how exposure to chronic psychological stress affects microglial activity within the prefrontal cortex (PFC) and, second, whether the observed changes were meaningfully related to corresponding changes in local neuronal activity and PFC-regulated behavior. Therefore, we examined markers of microglial activation, antigen presentation, apoptosis, and persistent neuronal activation within the PFC after exposure to repeated restraint stress. We also examined the effect of stress on spatial working memory, a PFC-dependent function. Finally, we tested the ability of a microglial activation inhibitor (minocycline) to alter the impact of chronic stress on all of these endpoints. Stressor exposure produced positively correlated increases in microglial and long-term neuronal activation in the PFC but not antigen presentation or apoptosis. As expected, it also impaired spatial working memory. Importantly, minocycline reduced the impact of stress on neuronal activation and working memory, as well as microglial activation. These results suggest a role for microglia in mediating the effects of stress on PFC neuronal function and PFC-regulated behavior.

Impact of cyclosporin on the incidence and prevalence of chronic rejection in renal transplants.

Over a 14-year period, 435 patients underwent renal transplantation. Chronic rejection has occurred in 58 (13%) of all grafts and has accounted for 18% of all graft losses. After the first 6 months following transplantation, chronic rejection was the most common cause of graft failure, accounting for 40% of losses. The median time (interquartile range) from transplantation to graft failure was 3 years (2-5.5 years). Comparison of azathioprine versus cyclosporin treated patients showed no significant difference in the incidence of graft loss (Cox regression score 2.55, P = 0.11). Furthermore, there were significantly more grafts with deteriorating function owing to chronic rejection in cyclosporin-treated patients (n = 16, 11% of surviving grafts) than in azathioprine-treated patients (n = 2, 3% of surviving grafts). These data suggest that cyclosporin does not prevent the development of chronic rejection in renal transplants.

A randomized placebo-controlled study of enalapril in the treatment of erythrocytosis after renal transplantation.

BACKGROUND: Erythrocytosis is a common complication of renal transplantation with an incidence of up to 17%. It is associated with an increased risk of complications due to thromboembolic events and has traditionally been treated by intermittent venesection. More recently, angiotensin-converting enzyme inhibitors have been shown to cause a fall in haematocrit in a number of groups of subjects and some uncontrolled studies have shown these drugs to be of possible therapeutic benefit in post renal transplant erythrocytosis. METHODS: We performed a randomized double-blind placebo-controlled study in 25 patients with post-transplant erythrocytosis. Subjects received either 2.5 mg of enalapril daily or a placebo for 4 months and all patients completed the study period without any serious adverse effects. RESULTS: Haematocrit fell from 52.7 (+/- SEM 0.7) to 47.1 (+/- 1.8) at 1 month and 46.1 (+/- 1.2) after 4 months in patients receiving enalapril, with no change in the placebo group (P = 0.004). We did not demonstrate any change in serum erythropoietin in either group. CONCLUSIONS: Angiotensin-converting enzyme inhibitors are a safe and effective form of treatment for erythrocytosis developing after renal transplantation. The mechanism of action, however, is not mediated by changes in erythropoietin production and remains uncertain.