Adenosine A(2A) Receptors in Bone Marrow-Derived Cells Attenuate Cognitive Impairment in Mice After Chronic Hypoperfusion White Matter Injury

The mechanism of cognitive dysfunction caused by ischemic white matter lesions is unclear. To explore the effect and mechanism of different cell-derived adenosine A(2A) receptor (A(2A)R) in cognitive impairment caused by chronic hypoperfusion white matter lesions (CHWMLs), we destroyed the bone marrow hematopoietic capacity of the recipient mice using radiation irradiation followed by establishing the selectively inactivated or reconstituted A(2A)R models with the transplanting bone marrow from global A(2A)R gene knockout or wild-type mice into wild-type or gene knockout mice, respectively. Then Morris Water Maze (MWM), ELISA, immunohistochemistry, and Bielschowsky silver staining were used to assess the effect and mechanism of the cognitive function in chronic cerebral blood flow hypoperfusion (CCH) model. Selectively reconstructing bone marrow-derived cells (BMDCs) A(2A)R (WT → KO group) and activated total adenosine A(2A)R with CGS21680 (CCH + CGS group) improved the cognitive related index. Activation of BMDC A(2A)R suppressed expression of inflammatory cytokines in peripheral blood and reduced the number of activated microglia cells co-localized with cystatin F in local brain, consequently inhibited white matter lesions. On the contrary, selective inactivation of adenosine A(2A)R (KO → WT group) and activation of non-BMDC A(2A)R with CGS21680 (KO → WT + CGS group) served the opposite effects. These results suggested that BMDC A(2A)R could inhibit white matter lesions and attenuate cognitive impairment after CHWMLs, whereas non-BMDC A(2A)Rs aggravate cognitive impairment. The systemic inflammatory response and local activated microglia with cystatin F high expression were involved in the process of cognitive function recovery with BMDC A(2A)R. The overall trend is that BMDC A(2A)Rs play a leading role. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12975-019-00778-9) contains supplementary material, which is available to authorized users.