MLC901 Favors Angiogenesis and Associated Recovery after Ischemic Stroke in Mice

Abstract

Background: There is increasing evidence that angiogenesis, through new blood vessel formation, results in improved collateral circulation and may impact the long-term recovery of patients. In this study, we first investigated the preventive action of a 5-week pretreatment of MLC901, an herbal extract preparation derived from Chinese medicine, against the deleterious effects of ischemic stroke and its effects on angiogenesis in a model of focal ischemia in mice. Methods: The stroke model was induced by 60 min of middle cerebral artery occlusion followed by reperfusion. MLC901 was administered in the drinking water of animals (6 g/l) for 5 weeks before ischemia and then during reperfusion. Results: MLC901 treatment increased the survival rate, reduced the cerebral infarct area and attenuated the blood brain barrier leakage as well as the neurologic dysfunction following ischemia and reperfusion. We provide evidence that MLC901 enhances endothelial cell proliferation and angiogenesis by increasing the number of neocortical vessels in the infarcted area. MLC901 regulates the expression of hypoxic inducible factor 1α and its downstream targets such as vascular endothelial growth factor and angiopoietins 1 and 2. This work also shows that erythropoietin is an important player in the enhancement of angiogenesis by MLC901. Conclusions: These results demonstrate therapeutic properties of MLC901, in addition to those previously described, in stimulating revascularization, neuroprotection and repair of the neurovascular unit after ischemic stroke.

Dual Effects of Chinese Herbal Medicines on Angiogenesis in Cancer and Ischemic Stroke Treatments: Role of HIF-1 Network

“…MLC901, an herbal extract preparation modified from the TCM herbal formula, has been proven to have neuroprotective and neurorestorative properties in preclinical models of stroke, traumatic brain injury, and global cerebral ischemia. Gandin et al (2016) found that 5-week pretreatment with MLC901 in MCAOinduced cerebral ischemia mouse models could regulate the expression of HIF-1α and its downstream targets, such as VEGF, Ang-1, and Ang-2. Chen et al showed that administration of TCM formula Bu Yang Huan Wu (BYHW) decoction decreased cerebral edema, the neurological deficient score, and brain infarct volume in a rat model of cerebral ischemia/reperfusion (I/R) injury.…”

“…Chinese herbal medicines often use a variety of herbs in different complex combinations to enhance their therapeutic effects or reduce their toxicity. Growing evidence has demonstrated potential proangiogenic benefits of Chinese herbal medicines in ischemic stroke whereas tumor angiogenesis could be inhibited by the active components in herbal medicines (Hong et al, 2015;Gandin et al, 2016;Hong et al, 2016;Guo et al, 2018). Thus, the objective of this review is to provide comprehensive insight on how Chinese herbal medicines impact angiogenesis by regulating HIF-1 pathways in both cancer and ischemic stroke.…”

Erythropoietin Restores Motor Functions through Angiogenesis in the Thalamus Area of Ischemic Stroke in Rats

“…A critical molecular pathway induced by hypoxia/ischemia is the activation of hypoxiainducible factor 1, a transcriptional activator of genes encoding VEGF and other important mediators of angiogenesis. Hif1 is the central transcriptional factor for the regulation of oxygen-associated genes in response to hypoxia (Gandin et al 2016). In the key restorative mechanisms in response to stroke, there is increasing evidences that angiogenesis, through new blood vessel formation, results in improved collateral circulation and may impact the long-term recovery of the patients (Gandin et al 2016).…”

Acute and long-term cardioprotective effects of the Traditional Chinese Medicine MLC901 against myocardial ischemia-reperfusion injury in mice

“…These beneficial effects have also been observed in an in vitro assay of oxygen-glucose deprivation that mimics brain ischemic conditions 25 . Both MLC601 and MLC901 are cocktail of molecules acting on many different targets such as free radical production (inhibition), ATP-sensitive K + channels (activation) 15 , 16 , 25 or HIF1α (Hypoxia-Inducible Factor 1-alpha), EPO (erythropoietin), VEGF (Vascular Endothelial Growth Factor) expression 26 .…”