Adenosine A1-Receptors Modulate mTOR Signaling to Regulate White Matter Inflammatory Lesions Induced by Chronic Cerebral Hypoperfusion

Abstract

We sought to investigate the role of the adenosine A1 receptors (A1ARs) in white matter lesions under chronic cerebral hypoperfusion (CCH) and explore the potential repair mechanisms by activation of the receptors. A right unilateral common carotid artery occlusion (rUCCAO) method was used to construct a CCH model. 2-chloro-N6-cyclopentyladenosine (CCPA), a specific agonist of A1ARs, was used to explore the biological mechanisms of repair in white matter lesions under CCH. The expression of mammalian target of rapamycin (mTOR), phosphorylation of mTOR (P-mTOR), myelin basic protein (MBP, a marker of white matter myelination) were detected by Western-blot. Pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) and anti-inflammatory cytokine interleukin-10 (IL-10) levels were determined by ELISA. Compared with the control groups on week 2, 4 and 6, in CCPA-treated groups, the ratio of P-mTOR/mTOR, expression of MBP and IL-10 increased markedly, while the expression of TNF-α reduced at week 6. In conclusion, A1ARs appears to reduce inflammation in white matter via the mTOR signaling pathway in the rUCCAO mice. Therefore, A1ARs may serve as a therapeutic target during the repair of white matter lesions under CCH.

Angiotensin IV suppresses inflammation in the brains of rats with chronic cerebral hypoperfusion

“…Emerging evidence has indicated that CCH is associated with an increased inflammatory response in the brain. 15 , 16 This may be a consequence of Aβ formation and tau hyperphosphorylation induced by CCH. 17 , 18 Although the inflammatory response is crucial for the brain to remove senescent cells and extrinsic pathogenic substances, long-lasting neuroinflammation is toxic to neurons and synapses, and thus contributes to neurodegeneration, white matter damage and cognitive impairments.…”

Fo-Shou-San Ameliorates Chronic Cerebral Hypoperfusion-Induced Cognitive Impairment in Mice by Regulating NRF2/HO-1 Pathway Against Ferroptosis

“…The same process without carotid ligation was operated on the sham group. Body temperature was sustained until mice were woken from anesthesia [39][40][41][42][43].…”

Limb Remote Ischemic Conditioning Promotes Myelination by Upregulating PTEN/Akt/mTOR Signaling Activities after Chronic Cerebral Hypoperfusion

“…The effects of anti-apoptosis and promoting oligodendrocytes proliferation, increasing myelin gene expression lead PI3K/Akt/mTOR pathway as one of essential signaling pathways during myelin growth [ 17 ]. Several studies showed that PI3K/Akt/mTOR signalings involved in white matter injuries after chronic cerebral hypoperfusion in rats [ 18 - 20 ].…”