Chaoren Koh

Introduction. Vascular dementia serves as the second most common cause of dementia after Alzheimer’s and consists of memory and cognitive deficits from reduced blood flow to the brain.^1,2 A prominent source of vascular dementia stems from cerebral small vessel diseases (CSVD).³ A mechanism of the disease involves chronic cerebral hypoperfusion (CCH) that leads to neuroinflammation in which microglia degrade white matter resulting in cognitive deficits.^4,5 These resident macrophages of the CNS can express either a M1 pro-inflammatory or M2 anti-inflammatory phenotype.^2,6,7 Researchers studied the role of TLR-4 and the complement C3/C3aR system in this process as well as thymoquinone as a potential novel therapeutic.^2,7,8 Methods. BCAS/BCCAO and SHRsp mice and rats were used to depict CCH and CSVD respectively.^2,7 Lipopolysaccharide stimulation of cultured microglia served to demonstrate in vivo effects.⁷ Quantitative PCR was utilized to measure mRNA levels of inflammatory and oxidative stress markers.⁸ Immunofluoresnces, electron microscopy, and Western blot were conducted to study autophagy activation in microglia.⁷ Microglia activation and the C3/C3aR pathway were studied with the help of CLARITY imaging and immunohistochemistry.² TLR-4 and C3aR knockout mice coupled with autophagy inhibitors and SB290157, a C3aR antagonist, were all utilized to examine the effects of these receptors on microglia activation and autophagy.^2,7 Morris water maze and new object recognition tests were carried out to examine cognitive abilities and behavior in mice and rats.^2,8 Results. Mice that experienced CCH displayed greater pro-inflammatory markers and M1 microglia type shown both in-vivo and in-vitro. TLR-4 knockout mice showed greater M2 microglia and myelin preservation. During CCH, LC3 II and beclin-1 (autophagy-related proteins) were upregulated but downregulated in TLR-4 knockout mice.⁷ C3 complements, which were also upregulated, bind to C3a receptors on microglia, activating them and directing them towards myelin to be phagocytized. C3aR knockout mice displayed decreased microglia activation and pro-inflammatory markers and mice given the C3aR antagonist displayed decreased amounts of microglia adhering to myelin.² Thymoquinone was shown to lower systolic blood pressure in a dose-dependent manner as well as decrease expressions of IL-1β, IL-6, MCP-1, and COX-2.^8,9 Thymoquinone was able to exhibit protective abilities against damage to memory and cognition in SHRsp rats.⁸ Conclusions. TLR-4 and the C3/C3aR complement system play a role in microglia activation and autophagy.^2,7 Potential strategies of therapeutics for CSVD and vascular dementia include controlling microglia activation and phenotype expression during CCH to prevent white matter damage and cognitive impairment.^2,7,8 Thymoquinone is also a potential candidate for treatment.⁸

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