Neuroscience
-
Rotenone is a pesticide that inhibits mitochondrial complex I activity, thus creating an environment of oxidative stress in the cell. Many studies have employed rotenone to generate an experimental animal model of Parkinson's disease (PD) that mimics and elicits PD-like symptoms, such as motor and cognitive decline. Cytoprotective proteins including parkin and heat shock proteins (HSPs) play major roles in slowing PD progression. ⋯ These protective proteins help maintain cellular homeostasis and may be capable of rescuing cells from death. Therefore, we assessed the levels of different HSPs in the rotenone-treated animals. Collectively, our studies indicated the following findings in the striatum and substantia nigra following chronic rotenone exposure in an experimental PD model: (i) behavioral deficit that correlated with histopathological changes and down regulation of TH signaling, (ii) decreased levels of the cytoprotective proteins parkin, DJ1 and Hsp70 and robust expression of mitochondrial chaperone Hsp60 according to Western blot, (iii) increased immunoreactivity for caspase 9, caspase 3 and ubiquitin and decreased parkin immunoreactivity.
-
Hepatic encephalopathy (HE) is a potentially fatal complication of acute liver failure, associated with severe neurological dysfunction and coma. The brain's innate immune cells, microglia, have recently been implicated in the pathophysiology of HE. To date, however, only ex vivo studies have been used to characterize microglial involvement. ⋯ Conversely, both microglial activation and motility are unchanged during AHE, despite the mice developing pathologically increased plasma ammonia and severe neurological dysfunction. Our study indicates that microglial activation does not contribute to the early neurological deterioration observed in either HE or AHE. The late microglial activation in HE may therefore be associated with terminal BBB opening and brain edema, thus exacerbating the progression to coma and increasing mortality.
-
A significant number of women suffer from depression during pregnancy and the postpartum period. Selective serotonin reuptake inhibitors (SSRIs) are commonly used to treat maternal depression. While maternal stress and depression have long-term effects on the physical and behavioural development of offspring, numerous studies also point to a significant action of developmental exposure to SSRIs. ⋯ Primary results show that developmental fluoxetine exposure, regardless of prenatal stress, decreases circulating levels of corticosterone and reduces the expression of the glucocorticoid receptor (GR), and its coactivator the GR interacting protein (GRIP1), in the hippocampus. Interestingly, these effects occurred primarily in male, and not in female, adolescent offspring. Together, these results highlight a marked sex difference in the long-term effect of developmental exposure to SSRI medications that may differentially alter the capacity of the hippocampus to respond to stress.
-
The perifornical-lateral hypothalamic area (PF-LHA) is a major wake-promoting structure. It predominantly contains neurons that are active during behavioral and cortical activation. Nitric oxide (NO) is a gaseous neurotransmitter that has been implicated in the regulation of sleep. ⋯ We found that NOC-18-induced suppression in the discharge activity of PF-LHA neurons was significantly attenuated during the blockade of adenosine A(1) receptor-, GABA(A) receptor-, and sGC-cGMP-mediated signaling. These findings suggest that NO-evoked inhibition of PF-LHA neurons involves a complex mechanism including, but may not be limited to, adenosinergic, GABAergic and sGC-cGMP signaling pathways. The findings are consistent with a generalized sleep-promoting role of NO within the PF-LHA and, given the sleep-promoting roles of adenosinergic and GABAergic systems in this area, further suggest that this effect may be mediated through nitrergic interactions with other neurotransmitters and neuromodulators.
-
Degradation of the extracellular matrix by elevated matrix metalloproteinase (MMP) activity following ischemia/reperfusion is implicated in blood-brain barrier disruption and neuronal death. In contrast to their characterized extracellular roles, we previously reported that elevated intranuclear MMP-2 and -9 (gelatinase) activity degrades nuclear DNA repair proteins and promotes accumulation of oxidative DNA damage in neurons in rat brain at 3-h reperfusion after ischemic stroke. Here, we report that treatment with a broad-spectrum MMP inhibitor significantly reduced neuronal apoptosis in rat ischemic hemispheres at 48-h reperfusion after a 90-min middle cerebral artery occlusion (MCAO). ⋯ We found a marked decrease in PARP1, XRCC1, and OGG1, and decreased PARP1 activity. Pretreatment of neurons with selective MMP-2/9 inhibitor II significantly decreased gelatinase activity and downregulation of DNA repair enzymes, decreased accumulation of oxidative DNA damage, and promoted neuronal survival after OGD. Our results confirm the nuclear localization of gelatinases and their nuclear substrates observed in an animal stroke model, further supporting a novel role for intranuclear gelatinase activity in an intrinsic apoptotic pathway in neurons during acute stroke injury.