FDCA Attenuates Neuroinflammation and Brain Injury after Cerebral Ischemic Stroke.

Ischemic stroke is a deleterious cerebrovascular disease with few therapeutic options, and its functional recovery is highly associated with the integrity of the blood-brain barrier and neuroinflammation. The Rho-associated coiled-coil containing protein kinase (ROCK) inhibitor fasudil (F) and the pyruvate dehydrogenase kinase (PDK) inhibitor dichloroacetate (DCA) have been demonstrated to exhibit neuroprotection in a series of neurological disorders. Hence, we synthesized and biologically examined the new salt fasudil dichloroacetate (FDCA) and validated that FDCA was eligible for attenuating ischemic volume and neurological deficits in the rat transient middle cerebral artery occlusion (tMCAO) model. Additionally, FDCA exerted superior effects than fasudil and dichloroacetate alone or in combination in reducing cerebral ischemic injury. Particularly, FDCA could maintain the blood-brain barrier (BBB) integrity by inhibiting matrix metalloproteinase 9 (MMP-9) protein expression and the degradation of zonula occludens (ZO-1) and Occludin protein. Meanwhile, FDCA could mitigate the neuroinflammation induced by microglia. The in vivo and in vitro experiments further demonstrated that FDCA disrupted the phosphorylations of myosin phosphatase target subunit 1 (MYPT1), mitogen-activated protein kinase (MAPK) cascade, including p38 and c-Jun N-terminal kinase (JNK), and pyruvate dehydrogenase (PDH) and limited excessive lactic acid metabolites, resulting in inhibition of BBB disruption and neuroinflammation. In addition, FDCA potently mitigated inflammatory response in human monocytes isolated from ischemic stroke patients, which provides the possibilities of a clinical translation perspective. Overall, these findings provided a therapeutic potential for FDCA as a candidate agent for ischemic stroke and other neurological diseases associated with BBB disruption and neuroinflammation.

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.

Effects of cerebroprotein hydrolysate for injection (II) on neuritogenesis and its underlying mechanisms / 中国药科大学学报

@#In most mammalian central nervous system diseases, axons are damaged.Due to the limited ability of damaged neurons to promote axonal regeneration, the formation of glial scar and the release of inhibitory nutrients, it is difficult to regenerate axons of damaged neurons. The purpose of this study was to investigate the effect of cerebroprotein hydrolysate for injection (II) (CBL) on neuritogenesis and its underlying mechanism. Immunofluorescence staining was used to detect the axon length of mouse neuroma cells (Neuro-2a) and mouse primary cortical neuronal cells. Western blotting was used to detect the expression of phosphorylated TrkB protein in Neuro-2a cells and mouse primary cortical neuronal cells. The results showed that CBL could increase the axon length of Neuro-2a cells or mouse primary cortical neuronal cells, and that the phosphorylation level of TrkB in neuronal cells was significantly increased when 5 μg/mL CBL was applied to neuronal cells for 1 h. In conclusion, CBL can promote neuritogenesis, and increase the expression of phosphorylated TrkB, which may be related to the activation of TrkB signaling pathway.