Microglia are resident macrophage-like immune cells in the central nervous system (CNS) and play a vital role in both physiological and pathological conditions, including restoring the integrity of the CNS and promoting the progression of neurodegenerative disorders. Upon stimulation, microglia typically convert from a surveillant to an activated phenotype. The major function of microglia is to maintain homeostasis and normal function of the CNS, both during development and in response to CNS injury. Microglia regulate multiple aspects of inflammation, such as repair, cytotoxicity, regeneration, and immunosuppression due to their different kind of activation states or phenotypes. Although microglia are involved in almost all neurodegenerative disorders, the mechanisms for microglial activation and their potential contributions to neuronal degeneration remain a matter of intense debate. In inflammatory process of the CNS, polarized M1 microglia can produce proinflammatory cytokines, neurotoxic molecules, which contribute to dysfunction of neural network and promoting inflammation reaction, whereas polarized M2 microglia secrete antiinflammatory mediators and neurotrophic factors that are involved in restoring homeostasis. Modulation of microglial activation for therapeutic purposes might be realized via suppressing the deleterious effects of these cells, while simultaneously retaining their protective functions. Here, we summarize the functions of microglia and discuss dual role of microglia in neurodegenerative diseases as well as multiple sclerosis.

Alzheimer's disease (AD) is a progressive neurodegenerative disease associated with senile beta-amyloid (Abeta) plaques and cognitive decline. Neurogenesis in the adult hippocampus is implicated in regulating learning and memory, and is increased in human postmortem brain of AD patients. However, little is currently known about the changes of hippocampal neurogenesis in the progression of AD. As brain tissues from patients during the progression of AD are generally not available, an amyloid precursor protein (APP)/presenilin1 (PS1) double transgenic mouse model of AD was studied. Bromodeoxyuridine (BrdU) labeling supported by doublecortin staining was used to detect proliferating hippocampal cells in the mice. Compared with age-matched wild-type controls, 9-month-old transgenic mice with memory impairment and numerous brain Abeta deposits showed increased numbers of proliferating hippocampal cells. However, 3-month-old transgenic mice with normal memory and subtle brain Abeta deposits showed normal hippocampal proliferation. Double immunofluorescent labeling with BrdU and either NeuN or glial fibrillary acidic protein was conducted in mice at 10 months (28 days after the last BrdU injection) to determine the differentiation of proliferating cells. The number of hippocampal BrdU-positive cells and BrdU-positive cells differentiating into neurons (neurogenesis) in 10-month-old mice was greater in transgenic mice compared with age-matched controls, but the ratio of hippocampal BrdU-positive cells differentiating into neurons and astroglia was comparable. These results suggest hippocampal neurogenesis may increase during the progression of AD. Targeting this change in neurogenesis and understanding the underlying mechanism could lead to the development of a new treatment to control the progression of AD.

No abstract

No abstract

No abstract

In patients with thrombotic stroke, the occluded artery often reopens over time. This results through a natural dissolution of the occluding material, and fragments of the material may move downstream to obstruct distal arteries. The current study was undertaken to investigate the patency of brain microvessels at varying time intervals after injection of a preformed clot into the right internal carotid artery of rats. Cerebral microvessels in brain sections were visualized using immunohistochemistry for fibronectin (detecting existing microvessels) and Evans blue (visualizing perfused microvessels). The percentage of patent microvessels was calculated as the number of Evans blue-positive microvessels divided by the number of fibronectin-positive microvessels. In normal control animals, results showed that 98% +/- 3% (mean +/- SD) of microvessels in the cortex and 94% +/- 14% in the striatum were patent. In the ischemic animals, immediately after clot injection, microvessels in the cortex and striatum were occluded, mainly in the territory irrigated by the middle cerebral artery. One hour after clot injection, microvessels had reopened in most of the cortex but remained occluded in some portions of the striatum, possibly as a result of downstream movement of fragments formed from the original clot. By 3 hours after clot injection, microvessels in the cortex were patent in all animals, whereas in the striatum microvessels were patent in 50% of the animals. In the other 50%, small striatal perfusion deficits persisted. At 24 hours after clot injection, microvessels were patent in both the cortex and striatum of all animals except one. These findings suggest that intracerebral clots dissolve spontaneously in a relatively short period of time, but that fragments formed from the clot may obstruct more distal blood vessels. It is likely that clot fragments lodge in arteries with lower blood flow and poor collateral perfusion, where they continue to cause ischemia for a longer duration. These results may in part explain the resistance of the striatum to neuroprotective strategies used for the treatment of focal cerebral ischemia.

No abstract

Oxidative stress is a key cause of ischemic stroke and an initiator of neuronal dysfunction and death, mainly through the overproduction of peroxides and the depletion of antioxidants. Ferroptosis/oxytosis is a unique, oxidative stress-induced cell death pathway characterized by lipid peroxidation and glutathione depletion. Both oxidative stress and ferroptosis/oxytosis have common molecular pathways. This review summarizes the possible targets and the mechanisms underlying the crosstalk between oxidative stress and ferroptosis/oxytosis in ischemic stroke. This knowledge might help to further understand the pathophysiology of ischemic stroke and open new perspectives for the treatment of ischemic stroke.