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Published on: November 22, 2024
Adenosine A2A receptor deficiency exacerbates white matter lesions and cognitive deficits induced by chronic cerebral
Wei Duan1, Li Gui, Zhujuan Zhou
1Department of Neurology, Xinqiao Hospital, Third Military Medical University, 2-V Xinqiao Street, Chongqing 400037, PR China.
Abstract:
Adenosine A2A receptor inactivation consistently protects against acute ischemic brain injury; however, the role of the A2A receptor in chronic cerebral ischemia is unknown. To elucidate that, chronic cerebral hypoperfusion model was established by permanent stenosis of bilateral common carotid artery in A2A receptor knock-out mice and their wild-type littermates in this study. White matter lesions were observed after stenosis of common carotid arteries in both A2A receptor knock-out mice and wild-type mice. The demyelination-related damage and proliferation of astrocytes and microglia in white matter was observed more seriously in A2A receptor knock-out mice compared with that in wild-type mice. Working memory was also more seriously impaired in A2A receptor knock-out mice relative to wild-type mice. The mRNA expression and protein level of proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and interleukin-6 (IL-6) increased more remarkably in the corpus callosum in the A2A receptor knock-out mice. In conclusion, inactivation of the A2A receptor exacerbates the white matter lesions and cognitive deficits induced by chronic cerebral hypoperfusion, and this effect may be associated with increased expression of the proinflammatory cytokines in the white matter.
Insights
Inactivating the Adenosine A2A receptor worsens white matter damage and cognitive decline in chronic cerebral ischemia. This exacerbation is linked to increased inflammatory responses in the brain.
Area of Science:
- Neuroscience
- Cerebrovascular Research
- Neuroinflammation
Background:
- Adenosine A2A receptor (A2AR) inactivation protects against acute ischemic brain injury.
- The role of A2AR in chronic cerebral ischemia remains largely unknown.
- Chronic cerebral hypoperfusion models are crucial for studying long-term effects of reduced blood flow to the brain.
Purpose of the Study:
- To investigate the role of the Adenosine A2A receptor in the context of chronic cerebral ischemia.
- To determine if A2AR inactivation impacts white matter integrity and cognitive function under conditions of sustained hypoperfusion.
Main Methods:
- Established a chronic cerebral hypoperfusion model in mice by permanent stenosis of bilateral common carotid arteries.
- Utilized A2A receptor knock-out (KO) mice and their wild-type (WT) littermates for comparison.
- Assessed white matter lesions, demyelination, glial cell proliferation (astrocytes and microglia), working memory, and expression of proinflammatory cytokines (TNF-alpha, IL-1beta, IL-6).
Main Results:
- Both A2AR KO and WT mice exhibited white matter lesions after carotid artery stenosis.
- A2AR KO mice showed more severe demyelination and glial cell proliferation in white matter compared to WT mice.
- Working memory impairment was significantly worse in A2AR KO mice.
- Increased mRNA and protein levels of TNF-alpha, IL-1beta, and IL-6 were observed in the corpus callosum of A2AR KO mice.
Conclusions:
- Inactivation of the Adenosine A2A receptor exacerbates white matter damage and cognitive deficits in chronic cerebral hypoperfusion.
- This detrimental effect appears to be associated with heightened expression of proinflammatory cytokines within the white matter.
