pexidartinib and Cognitive-Dysfunction

Cognitive decline occurs frequently in Parkinson's disease (PD), which greatly decreases the quality of life of patients. However, the mechanisms remain to be investigated. Neuroinflammation mediated by overactivated microglia is a common pathological feature in multiple neurological disorders, including PD. This study is designed to explore the role of microglia in cognitive deficits by using a rotenone-induced mouse PD model.. To evaluate the role of microglia in rotenone-induced cognitive deficits, PLX3397, an inhibitor of colony-stimulating factor 1 receptor, and minocycline, a widely used antibiotic, were used to deplete or inactivate microglia, respectively. Cognitive performance of mice among groups was detected by Morris water maze, objective recognition, and passive avoidance tests. Neurodegeneration, synaptic loss, α-synuclein phosphorylation, glial activation, and apoptosis were determined by immunohistochemistry and Western blot or immunofluorescence staining. The gene expression of inflammatory factors and lipid peroxidation were further explored by using RT-PCR and ELISA kits, respectively.. Rotenone dose-dependently induced cognitive deficits in mice by showing decreased performance of rotenone-treated mice in the novel objective recognition, passive avoidance, and Morris water maze compared with that of vehicle controls. Rotenone-induced cognitive decline was associated with neurodegeneration, synaptic loss, and Ser129-phosphorylation of α-synuclein and microglial activation in the hippocampal and cortical regions of mice. A time course experiment revealed that rotenone-induced microglial activation preceded neurodegeneration. Interestingly, microglial depletion by PLX3397 or inactivation by minocycline significantly reduced neuronal damage and α-synuclein pathology as well as improved cognitive performance in rotenone-injected mice. Mechanistically, PLX3397 and minocycline attenuated rotenone-induced astroglial activation and production of cytotoxic factors in mice. Reduced lipid peroxidation was also observed in mice treated with combined PLX3397 or minocycline and rotenonee compared with rotenone alone group. Finally, microglial depletion or inactivation was found to mitigate rotenone-induced neuronal apoptosis.. Taken together, our findings suggested that microglial activation contributes to cognitive impairments in a rotenone-induced mouse PD model via neuroinflammation, oxidative stress, and apoptosis, providing novel insight into the immunopathogensis of cognitive deficits in PD.

Topics: Aminopyridines; Animals; Cognitive Dysfunction; Insecticides; Male; Mice; Mice, Inbred C57BL; Microglia; Minocycline; Parkinsonian Disorders; Pyrroles; Rotenone

Delayed cognitive decline commonly occurs following intracerebral hemorrhage (ICH), but the mechanisms underlying this phenomenon remain obscure. We therefore investigated the potential mechanisms responsible for impaired cognitive function in a mouse collagenase model of ICH. Following recovery of motor and sensory deficits in the chronic phase of ICH, we noted significant cognitive impairment, which was assessed by the Morris water maze. This finding was accompanied by reduced dendrite spine density of ipsilateral hippocampal CA1 neurons. Reduced synaptic plasticity, manifested by impaired long-term potentiation in hippocampal neurons, was also evident in both ipsilateral and contralateral hemispheres, suggesting that ICH also induces functional alterations in distal brain regions remote from the site of injury. In addition, the accumulation of microglia, infiltration of peripheral immune cells, and generation of reactive oxygen species were observed in both contralateral and ipsilateral hemispheres up to 5 wk post-ICH. Furthermore, depletion of microglia using PLX3397, which inhibits colony stimulating factor 1 receptor, ameliorated this delayed cognitive impairment. Collectively, these results suggest that persistent and diffuse brain inflammation may contribute to cognitive impairment in the chronic stage of ICH recovery.-Shi, E., Shi, K., Qiu, S., Sheth, K. N., Lawton, M. T., Ducruet, A. F. Chronic inflammation, cognitive impairment, and distal brain region alteration following intracerebral hemorrhage.

Topics: Aminopyridines; Animals; Brain; Cerebral Hemorrhage; Cognition; Cognitive Dysfunction; Disease Models, Animal; Fingolimod Hydrochloride; Flow Cytometry; Hippocampus; Inflammation; Male; Mice; Mice, Inbred C57BL; Microglia; Neuroimaging; Neuronal Plasticity; Pyrroles; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor