No abstract

Blood-brain barrier preservation plays an important role in attenuating vasogenic brain edema after subarachnoid hemorrhage (SAH). This study was designed to investigate the protective effect and mechanism of artesunate, a traditional anti-malaria drug, on blood-brain barrier after SAH. Three hundred and seventy-seven (377) male Sprague-Dawley rats were subjected to endovascular perforation model for SAH. The rats received artesunate alone or in combination with Sphingosine-1-phosphate receptor-1 (S1P1) small interfering RNA (siRNA), antagonist VPC23019, or phosphatidylinositol 3-kinase inhibitor wortmannin after SAH. Modified Garcia score, SAH grades, brain water content, Evans blue leakage, transmission electron microscope, immunohistochemistry staining, Western blot, and cultured endothelial cells were used to investigate the optimum concentration and the therapeutic mechanism of artesunate. We found that artesunate (200 mg/kg) could do better in raising modified Garcia score, reducing brain water content and Evans blue leakage than other groups after SAH. Moreover, artesunate elevated S1P1 expression, enhanced phosphatidylinositol 3-kinase activation, lowered GSK-3β activation, stabilized β-catenin, and improved the expression of Claudin-3 and Claudin-5 after SAH in rats. These effects were eliminated by S1P1 siRNA, VPC23019, and wortmannin. This study revealed that artesunate could preserve blood-brain barrier integrity and improve neurological outcome after SAH, possibly through activating S1P, enhancing phosphatidylinositol 3-kinase activation, stabilizing β-catenin via GSK-3β inhibition, and then effectively raising the expression of Claudin-3 and Claudin-5. Therefore, artesunate may be favorable for the blood-brain barrier (BBB) protection after SAH and become a potential candidate for the treatment of SAH patients.

Artesunate is an important agent for cerebral malaria and all kinds of other severe malaria because it is highly efficient, lowly toxic, and well-tolerated. Loads of research pointed out that it had widespread pharmacological activities such as antiparasites, antitumor, anti-inflammation, antimicrobes activities. As we know, the occurrence and development of neurological disorders usually refer to intricate pathophysiologic mechanisms and multiple etiopathogenesis. Recent progress has also demonstrated that drugs with single mechanism and serious side-effects are not likely the candidates for treatment of the neurological disorders. Therefore, the pluripotent action of artesunate may result in it playing an important role in the prevention and treatment of these neurological disorders. This review provides an overview of primary pharmacological mechanism of artesunate and its potential therapeutic effects on neurological disorders. Meanwhile, we also briefly summarize the primary mechanisms of artemisinin and its derivatives. We hope that, with the evidence presented in this review, the effect of artesunate in prevention and curing for neurological disorders can be further explored and studied in the foreseeable future.

Cerebral white matter lesion (WML) is one of the main causes for cognitive impairment and is often caused by chronic cerebral hypoperfusion. A line of evidence has shown that aspirin has neuroprotective effects and produces some benefits in long-term outcome and survival for ischemic stroke patients. However, whether aspirin exerts a protective effect against WML is still largely unknown. Here, we showed that aspirin could promote oligodendrocyte precursor cell (OPC) proliferation and differentiation into oligodendrocytes after WML. Male Sprague-Dawley rats were subjected to permanent bilateral common carotid artery occlusion, a well-established model for WML. Four weeks later, Morris water maze test showed an impairment of learning and memory ability of rat while aspirin treatment improved behavioral performance. Low dose of aspirin (25 mg/kg) was found to elevate the number of OPCs while relatively high doses (100–200 mg/kg) increased that of oligodendrocytes, and ameliorated WML-induced the thinning of myelin, as revealed by the electron microscope. Similarly, our in vitro study also showed that relatively low and high doses of aspirin enhanced OPC proliferation and differentiation into oligodendrocytes, respectively. Furthermore, we revealed that aspirin enhanced extracellular signal-related kinase (ERK) but inhibited RhoA activities. In summary, we provided the first evidence that aspirin can promote oligodendrogenesis and oligodendrocyte myelination after WML, which may involve ERK and RhoA pathways.

Subarachnoid hemorrhage (SAH) usually results from ruptured aneurysm, but how leaked hemoglobin regulates the microcirculation in the pathophysiology of early brain injury after SAH is still unclear. In the present study, we sought to investigate the role and possible mechanism of hemoglobin induced pericyte phenotype transformation in the regulation of microcirculation after SAH. Endovascular perforation SAH rat model, brain slices and cultured pericytes were used, and intervened with endothelial nitric oxide synthase (eNOS) antagonist L-NNA and its agonist scutellarin, hemoglobin, DETA/NO (nitric oxide(NO) donor), PITO (NO scavenger), 8-Br-cGMP (cGMP analog). We found modulating eNOS regulated pericyte α-SMA phenotype transformation, microcirculation, and neurological function in SAH rats. Modulating eNOS also affected eNOS expression, eNOS activity and NO availability after SAH. In addition, we showed hemoglobins penetrated into brain parenchyma after SAH. And hemoglobins significantly reduced the microvessel diameters at pericyte sites, due to the effects of hemoglobin inducing α-SMA expressions in cultured pericytes and brain slices via inhibiting NO/cGMP pathway. In conclusion, pericyte α-SMA phenotype mediates acute microvessel constriction after SAH possibly by hemoglobin suppressing NO/cGMP signaling pathway. Therefore, by targeting the eNOS and pericyte α-SMA phenotype, our present data may shed new light on the management of SAH patients.

Objective The potential roles and mechanisms of pericytes in maintaining blood–brain barrier (BBB) integrity, which would be helpful for the development of therapeutic strategies for subarachnoid hemorrhage (SAH), remain unclear. We sought to provide evidence on the potential role of pericytes in BBB disruption and possible involvement and mechanism of CypA signaling in both cultured pericytes and SAH models. Methods Three hundred fifty-three adult male C57B6J mice weighing 22 to 30 g, 29 CypA−/− mice, 30 CypA+/+ (flox/flox) mice, and 30 male neonatal C57B6J mice were used to investigate the time course of CypA expression in pericytes after SAH, the intrinsic function and mechanism of CypA in pericytes, and whether the known receptor CD147 mediates these effects. Results Our data demonstrated both intracellular CypA and CypA secretion increased after SAH and could activate CD147 receptor and downstream NF-κB pathway to induce MMP9 expression and proteolytic functions for degradation of endothelium tight junction proteins and basal membranes. CypA served as autocrine or paracrine ligand for its receptor, CD147. Although CypA could be endocytosed by pericytes, specific endocytosis inhibitor chlorpromazine did not have any effect on MMP9 activation. However, specific knockdown of CD147 could reverse the harmful effects of CypA expression in pericytes on the BBB integrity after SAH. Conclusions This study demonstrated for the first time that CypA mediated the harmful effects of pericytes on BBB disruption after SAH, which potentially mediated by CD147/NF-κB/MMP9 signal, and junction protein degradation in the brain. By targeting CypA and pericytes, this study may provide new insights on the management of SAH patients.

Hypertensive intracerebral hemorrhage (ICH) could very probably trigger white matter injury in patients. Through the continuous study of white matter injury after hypertensive ICH, we achieve a more profound understanding of the pathophysiological mechanism of its occurrence and development. At the same time, we found a series of drugs and treatment methods for the white matter repair. In the current reality, the research paradigm of white matter injury after hypertensive ICH is relatively obsolete or incomplete, and there are still lots of deficiencies in the research. In the face of the profound changes of stroke research perspective, we believe that the combination of the lenticulostriate artery, nerve nuclei of the hypothalamus-thalamus-basal ganglia, and the white matter fibers located within the capsula interna will be beneficial to the research of white matter injury and repair. This paper has classified and analyzed the study of white matter injury and repair after hypertensive ICH and also rethought the shortcomings of the current research. We hope that it could help researchers further explore and study white matter injury and repair after hypertensive ICH.

Progressive white matter (WM) impairments caused by subarachnoid hemorrhage (SAH) contribute to cognitive deficits and poor clinical prognoses; however, their pathogenetic mechanisms are poorly understood. We investigated the role of nexilin and oligodendrocyte progenitor cell (OPC)-mediated repair in a mouse model of experimental SAH generated via left endovascular perforation. Nexilin expression was enhanced by the elevated migration of OPCs after SAH. Knocking down nexilin by siRNA reduced OPC migration both in vitro and in vivo and abridged WM repair. In contrast, the protease-activated receptor 1 (PAR1), Ras-proximate-1 (RAP1) and phosphorylated RAP1 (pRAP1) levels in WM were elevated after SAH. The genetic inhibition of PAR1 reduced RAP1 and pRAP1 expression, further enhancing nexilin expression. When delivered at an early stage at a concentration of 25 µg/kg, thrombin receptor antagonist peptide along with PAR1 knockdown rescued the down-regulation of myelin basic protein and improved remyelination at the later stage of SAH. Our results suggest that nexilin is required for OPC migration and remyelination following SAH, as it negatively regulates PAR1/RAP1 signaling, thus providing a promising therapeutic target in WM repair and functional recovery.