Molecular mechanisms underlying the role of statins in the induction of brain plasticity and subsequent improvement of neurologic outcome after treatment of stroke have not been adequately investigated. Here, we use both in vivo and in vitro studies to investigate the potential roles of two prominent factors, vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF), in mediating brain plasticity after treatment of stroke with atorvastatin. Treatment of stroke in adult mice with atorvastatin daily for 14 days, starting at 24 hours after MCAO, shows significant improvement in functional recovery compared with control animals. Atorvastatin increases VEGF, VEGFR2 and BDNF expression in the ischemic border. Numbers of migrating neurons, developmental neurons and synaptophysin-positive cells as well as indices of angiogenesis were significantly increased in the atorvastatin treatment group, compared with controls. In addition, atorvastatin significantly increased brain subventricular zone (SVZ) explant cell migration in vitro. Anti-BDNF antibody significantly inhibited atorvastatin-induced SVZ explant cell migration, indicating a prominent role for BDNF in progenitor cell migration. Mouse brain endothelial cell culture expression of BDNF and VEGFR2 was significantly increased in atorvastatin-treated cells compared with control cells. Inhibition of VEGFR2 significantly decreased expression of BDNF in brain endothelial cells. These data indicate that atorvastatin promotes angiogenesis, brain plasticity and enhances functional recovery after stroke. In addition, VEGF, VEGFR2 and BDNF likely contribute to these restorative processes.
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"VEGF is a neurotrophic factor that regulates neuronal survival, neurogenesis and brain vascular remodeling. VEGF is secreted by astrocytes at basal levels under physiological conditions, and at higher levels after hypoxia (Sinor et al., 1998; Chow et al., 2001; Chen et al., 2005). VEGF can mediate both neuroprotection, by the stimulation of angiogenesis (Jin et al., 2002), and neuronal damage, as its upregulation may induce increased BBB leakage and increase the lesioned area especially during the acute stage of ischemic injury (Zhang et al., 2000). "
[Show abstract][Hide abstract]ABSTRACT: Stroke and traumatic injuries of the brain and spinal cord are major public health issues. In the last few decades, hundreds of clinical trials with patients suffering from these conditions have been done, however, most of them had not succeeded and there is still the need to develop more effective treatments for these conditions. Astrocytes play critical roles in the development, function and survival of neurons in the central nervous system. These cells are implicated in the pathophysiology and in the response to several neuropathological conditions and may represent potential cell targets for neuroprotective strategies. Progesterone and dehydroepiandrosterone (DHEA) are neuroactive steroids that modulate neuronal and astroglial function and have neuroprotective effects in different experimental models, being potential candidates to the development of new therapeutic approaches for brain and spinal cord injuries. The aim of this review is to discuss the role of astrocytes in the pathophysiology of brain and spinal cord injuries and how they could be modulated by progesterone and DHEA for the treatment of these conditions.
Full-text · Article · Apr 2016 · Progress in Neurobiology
"Brown, Aminoltejari, Erb, Winship & Murphy, 2009). Increases in BDNF (J. Chen et al., 2005), neurogenesis (Zhang, Zhang & Chopp, 2008), and the formation of new synapses (Warraich & Kleim, 2010) have also been shown after stroke. As with TBI, formal rehabilitation is key for recovery following stroke. "
[Show abstract][Hide abstract]ABSTRACT: The role of neuroplasticity, or the brain’s ability to modify neural processes as a result of environmental changes, is crucial to normal memory functioning. Furthermore, this capacity of the central nervous system to adapt is essential for healthy aging and for recovery following trauma or disease states. In this chapter, we identify the synaptic and structural mechanisms that drive plasticity, as well as describe the purported processes responsible for short- and long-term memory. We then review the literature regarding the role of neuroplasticity in the aging brain and in recovery following various types of injury (e.g., traumatic brain injury and stroke). Particular focus is placed on the implications of lifestyle factors, such as diet, exercise, and environmental enrichment, and formal cognitive training or rehabilitation strategies as potential methods for facilitating neuroplasticity and maintaining healthy memory functioning.
"The relationship between BDNF and synaptogenesis is widely studied. Chen et al.  have shown that statin, a BDNF upregulation inductor, is related to an increase of synaptophysin expression and to functional recovery after stroke. Pozzo-Miller et al.  have shown that BDNF knockout mice have a reduced level of synaptophysin in hippocampal synaptosomes. "
[Show abstract][Hide abstract]ABSTRACT: Polyphenols have neuroprotective effects after brain ischemia. It has been demonstrated that rosmarinic acid (RA), a natural phenolic compound, possesses antioxidant and anti-inflammatory properties. To evaluate the effectiveness of RA against memory deficits induced by permanent middle cerebral artery occlusion (pMCAO) mice were treated with RA (0.1, 1, and 20mg/kg/day, i. p. before ischemia and during 5 days). Animals were evaluated for locomotor activity and working memory 72h after pMCAO, and spatial and recognition memories 96h after pMCAO. In addition, in another set of experiments brain infarction, neurological deficit score and myeloperoxidase (MPO) activity were evaluates 24h after the pMCAO. Finally, immunohistochemistry, and western blot, and ELISA assay were used to analyze glial fibrillary acidic protein (GFAP), and synaptophysin (SYP) expression, and BDNF level, respectively. The working, spatial, and recognition memory deficits were significantly improved with RA treatment (20mg/kg). RA reduced infarct size and neurological deficits caused by acute ischemia. The mechanism for RA neuroprotection involved, neuronal loss suppression, and increase of synaptophysin expression, and increase of BDNF. Furthermore, the increase of MPO activity and GFAP immunireactivity were prevented in MCAO group treated with RA. These results suggest that RA exerts memory protective effects probably due to synaptogenic activity and anti-inflammatory action.
Full-text · Article · Oct 2015 · Behavioural brain research