Brain research
-
Positive allosteric modulators (PAMs) for the α7 nicotinic receptor hold promise for the treatment of sensory inhibition deficits observed in schizophrenia patients. Studies of these compounds in the DBA/2 mouse, which models the schizophrenia-related deficit in sensory inhibition, have shown PAMs to be effective in improving the deficit. However, the first published clinical trial of a PAM for both sensory inhibition deficits and related cognitive difficulties failed, casting a shadow on this therapeutic approach. ⋯ However, combining the lowest doses of both PNU-120596 and choline chloride in this mouse model did improve sensory inhibition. We propose here that the difference in efficacy of PNU-120596 between the 2 mouse strains is driven by differences in hippocampal α7 nicotinic receptor numbers, such that C3H Chrna7 heterozygote mice require additional direct stimulation of the α7 receptors. These data may have implications for further clinical testing of putative α7 nicotinic receptor PAMs.
-
Traumatic brain injury (TBI) is a major contributor to mortality and morbidity. The pathophysiology involves development of brain edema. Therapeutic options are limited as the mechanisms are not fully understood. ⋯ The total amount of AQP4 protein decreased (-20%). The disruption of the BBB lasted for 4 days while the impact on AQP4 levels disappeared between day 1 and 4. Our findings shows that blunt focal brain injury results in an early development of brain edema involving both cytotoxic and vasogenic components, a persistent BBB breakdown and a temporary decrease in AQP4, and indicates that both types of edemas and mechanisms should be targeted in TBI treatment.
-
Caloric restriction (CR) has been shown to have several health benefits and provides protection against type 2 diabetes, neurodegenerative and cerebral vascular diseases. It reduces the brain infarct size and promotes neurological functional recovery after cerebral ischemia. Sirtuin 1 (SIRT1) plays an important role in the biological effects induced by CR. ⋯ CR increased the synthesis of SIRT1 significantly (p < 0.05), and ameliorated the down regulation of SIRT1 expression at 6 and 12h after middle cerebral artery occlusion (p < 0.05, p < 0 .01, respectively). Knockdown of SIRT1 by siRNA in vivo reversed the neuroprotective effect of CR. From this study, we deduce that CR induces brain ischemic tolerance on rats via increasing the synthesis of SIRT1.
-
Receptor-interacting protein 3 (RIP3) is a key molecular switch in tumor necrosis factor-induced necroptosis requiring the formation of an RIP3-RIP1 complex. We have recently shown that hippocampal cornu ammonis 1 (CA1) neuronal death induced by 20-min global cerebral ischemia/reperfusion (I/R) injury is a form of programmed necrosis. However, the mechanism behind this process is still unclear and was studied here. ⋯ Decreased level of NAD+ in hippocampus and the release of cathepsin-B from lysosomes after I/R injury were also inhibited by Nec-1. Our data demonstrate that Nec-1 inhibits neuronal death by preventing RIP3 upregulation and nuclear translocation, as well as NAD+ depletion and cathepsin-B release. The nuclear translocation of RIP3 has not been reported previously, so this may be an important role for RIP3 during ischemic injury.
-
Chronic pain is a pathological condition that results in significant loss of life quality, but so far no specific treatment for chronic pain has been developed. Currently available analgesia drugs are either not specific enough or have severe side effects. Therefore a non-invasive approach with high specificity to inhibit nociception becomes essential. ⋯ In vivo behavioral tests demonstrated that both the mechanical paw withdrawal threshold and the radiant heat evoked paw withdrawal latency were significantly increased upon illumination by a 532 nm green laser light to the paw of a viral-vector injected mice, while the same laser light did not induce any observable change in naïve mice. In conclusion, we have established a novel analgesic approach that can noninvasively and selectively inhibit pain transmission using an acute and controllable optogenetics method. This study may shed light on the application of a novel optogenetic strategy for the treatment of pain.