A Novel Hybrid of Telmisartan and Borneol Ameliorates Neuroinflammation and White Matter Injury in Ischemic Stroke Through ATF3/CH25H Axis

Cerebral ischemic stroke causes substantial white matter injury, which is further aggravated by neuroinflammation mediated by microglia/astrocytes. Given the anti-neuroinflammatory action of telmisartan and the enhancing blood-brain barrier (BBB) permeability potential of resuscitation-inducing aromatic herbs, 13 hybrids (3a-m) of telmisartan (or its simplified analogues) with resuscitation-inducing aromatic agents were designed, synthesized, and biologically evaluated. Among them, the optimal compound 3a (the ester hybrid of telmisartan and (+)-borneol) potently inhibited neuroinflammation mediated by microglia/astrocytes and ameliorated ischemic stroke. Particularly, 3a significantly conferred protection for white matter integrity after cerebral ischemic stroke via decreasing abnormally dephosphorylated neurofilament protein, upregulating myelin basic protein, and attenuating oligodendrocyte damage. Further RNA-sequencing data revealed that 3a upregulated expression of transcriptional regulator ATF3 to reduce the expression of CH25H, prevented proinflammatory state of lipid-droplet-accumulating microglia/astrocytes to limit excessive inflammation, and eventually protected neighboring oligodendrocytes to prevent white matter injury. Taken with the desirable pharmacokinetics behavior and improved brain distribution, 3a may be a feasible therapeutic agent for ischemic stroke and other neurological disorders with white matter injury.