Neurogenesis in the aging brain

Neurogenesis, or the birth of new neural cells, was thought to occur only in the developing nervous system and a fixed neuronal population in the adult brain was believed to be necessary to maintain the functional stability of adult brain circuitry. However, recent studies have demonstrated that neurogenesis does indeed continue into and throughout adult life in discrete regions of the central nervous systems (CNS) of all mammals, including humans. Although neurogenesis may contribute to the ability of the adult brain to function normally and be induced in response to cerebral diseases for self-repair, this nevertheless declines with advancing age. Understanding the basic biology of neural stem cells and the molecular and cellular regulation mechanisms of neurogenesis in young and aged brain will allow us to modulate cell replacement processes in the adult brain for the maintenance of healthy brain tissues and for repair of disease states in the elderly

Contra-Directional Expression of Serum Homocysteine and Uric Acid as Important Biomarkers of Multiple System Atrophy Severity: A Cross-Sectional Study

Aims. There is evidence suggesting that inflammatory responses play a critical role in the pathogenesis of multiple system atrophy (MSA). Whether inflammatory mediators can be used as reliable biomarkers to detect the severity and progression of MSA remains largely unknown. Methods. We performed a cross-sectional study that included 47 patients with MSA and 50 healthy age-matched controls. Serum levels of homocysteine (Hcy), uric acid (UA) and C-reactive protein (CRP) were measured. These levels positively correlated with the severity of MSA, based on both motor and non-motor symptoms (NMS). Several scales were used to rate the severity of MSA, including the Unified multiple system atrophy rating scale (UMSARS), Parkinson’s disease sleep scale (PDSS), Non-motor Symptoms Scale (NMSS), the Schwab & England Activities of Daily Living Scale (ADL), Webster Scale, modified Hoehn and Yahr staging scale (H&Y), and the Mini-Mental State Examination (MMSE). Receiver Operating Characteristic (ROC) curves was applied to map the diagnostic accuracy of MSA against healthy subjects. Results. Compared with healthy subjects, we found that serum Hcy was higher, UA was lower, and CRP levels were unchanged in MSA patients. These findings were especially prominent in male patients. No significant differences of serum Hcy and UA were observed between patients of MSA and PD. Interestingly, there was a significant correlation between Hcy levels and MSA severity such as movement dysfunction, declined cognition, and cardiovascular symptoms. Additionally, the ROC curve for the combination of Hcy and UA (AUC 0.736) showed potential diagnostic value in discriminating MSA from healthy subjects. Conclusions. Our findings suggest that the inflammatory mediators Hcy and UA may play important roles in the pathogenesis of MSA. The measurement of serum Hcy and UA levels could then be a useful tool to accurately distinguish MSA from healthy subjects

Microglia exacerbate white matter injury via complement C3/C3aR pathway after hypoperfusion.

Microglial activation participates in white matter injury after cerebral hypoperfusion. However, the underlying mechanism is unclear. Here, we explore whether activated microglia aggravate white matter injury via complement C3-C3aR pathway after chronic cerebral hypoperfusion. Methods: Adult male Sprague-Dawley rats (n = 80) underwent bilateral common carotid artery occlusion for 7, 14, and 28 days. Cerebral vessel density and blood flow were examined by synchrotron radiation angiography and three-dimensional arterial spin labeling. Neurobehavioral assessments, CLARITY imaging, and immunohistochemistry were performed to evaluate activation of microglia and C3-C3aR pathway. Furthermore, C3aR knockout mice were used to establish the causal relationship of C3-C3aR signaling on microglia activation and white matter injury after hypoperfusion. Results: Cerebral vessel density and blood flow were reduced after hypoperfusion (p<0.05). Spatial learning and memory deficits and white matter injury were shown (p<0.05). These impairments were correlated with aberrant microglia activation and an increase in the number of reactive microglia adhering to and phagocytosed myelin in the hypoperfusion group (p<0.05), which were accompanied by the up-regulation of complement C3 and its receptors C3aR (p<0.05). Genetic deletion of C3ar1 significantly inhibited aberrant microglial activation and reversed white matter injury after hypoperfusion (p<0.05). Furthermore, the C3aR antagonist SB290157 decreased the number of microglia adhering to myelin (p<0.05), attenuated white matter injury and cognitive deficits in chronic hypoperfusion rats (p<0.05). Conclusions: Our results demonstrated that aberrant activated microglia aggravate white matter injury via C3-C3aR pathway during chronic hypoperfusion. These findings indicate C3aR plays a critical role in mediating neuroinflammation and white matter injury through aberrant microglia activation, which provides a novel therapeutic target for the small vessel disease and vascular dementia

Role for Neuronal Nitric-Oxide Synthase in Cannabinoid-Induced Neurogenesis

ABSTRACT Cannabinoids, acting through the CB1 cannabinoid receptor (CB1R), protect the brain against ischemia and related forms of injury. This may involve inhibiting the neurotoxicity of endogenous excitatory amino acids and downstream effectors, such as nitric oxide (NO). Cannabinoids also stimulate neurogenesis in the adult brain through activation of CB1R. Because NO has been implicated in neurogenesis, we investigated whether cannabinoid-induced neurogenesis, like cannabinoid neuroprotection, might be mediated through alterations in NO production. Accordingly, we measured neurogenesis in dentate gyrus (DG) and subventricular zone (SVZ) of CB1R-knockout (KO) and wild-type mice, some of whom were treated with the cannabi- or the NO synthase (NOS) inhibitor 7-nitroindazole (7-NI). NOS activity was increased by ϳ25%, whereas bromodeoxyuridine (BrdU) labeling of newborn cells in DG and SVZ was reduced by ϳ50% in CB1R-KO compared with wild-type mice. 7-NI increased BrdU labeling in both DG and SVZ and to a greater extent in CB1R-KO than in wild-type mice. In addition, R(ϩ)-Win 55212-2 and 7-NI enhanced BrdU incorporation into neuron-enriched cerebral cortical cultures to a similar maximal extent and in nonadditive fashion, consistent with a shared mechanism of action. Double-label confocal microscopy showed coexpression of BrdU and the neuronal lineage marker doublecortin (Dcx) in DG and SVZ of untreated and 7-NI-treated CB1R-KO mice, and 7-NI increased the number of Dcx-and BrdU/Dcx-immunoreactive cells in SVZ and DG. Thus, cannabinoids appear to stimulate adult neurogenesis by opposing the antineurogenic effect of NO. Cannabinoids, which include naturally occurring plantderived compounds [e.g., ⌬ 9 -tetrahydrocannabinol (THC)], endogenous signaling molecules found in animal brains (e.g., anandamide and 2-arachidonoylglycerol), and synthetic drugs [e.g., R(ϩ)-Win 55212-2)], act on receptors in the brain to modify neuronal function. In addition to their effects on normal physiological functions such as blood pressure, immunity, pain perception, appetite, and cognition, cannabinoids can also regulate the severity of brain injury. We reported previously that administration of cannabinoids acting on the CB1 cannabinoid receptor (CB1R) reduces neuronal death from cerebral ischemi

Defective adult neurogenesis in CB1 cannabinoid receptor knockout mice.

ABSTRACT Pharmacological studies suggest a role for CB1 cannabinoid receptors (CB1R) in regulating neurogenesis in the adult brain. To investigate this possibility, we measured neurogenesis by intraperitoneal injection of bromodeoxyuridine (BrdU), which labels newborn neurons, in wild-type and CB1R-knockout (CB1R-KO) mice. CB1R-KO mice showed reductions in the number of BrdU-labeled cells to ϳ50% of wild-type (WT) levels in dentate gyrus and subventricular zone (SVZ), suggesting that CB1R activation promotes neurogenesis. To test this further, WT mice were given the CB1R antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR141716A) before measuring neurogenesis with BrdU

Exosomes Derived From Bone Mesenchymal Stem Cells Ameliorate Early Inflammatory Responses Following Traumatic Brain Injury

Traumatic brain injury (TBI) is a leading cause of mortality and disability worldwide. Although treatment guidelines have been developed, no best treatment option or medicine for this condition exists. Recently, mesenchymal stem cells (MSCs)-derived exosomes have shown lots of promise for the treatment of brain disorders, with some results highlighting the neuroprotective effects through neurogenesis and angiogenesis after TBI. However, studies focusing on the role of exosomes in the early stages of neuroinflammation post-TBI are not sufficient. In this study, we investigated the role of bone mesenchymal stem cells (BMSCs)-exosomes in attenuating neuroinflammation at an early stage post-TBI and explored the potential regulatory neuroprotective mechanism. We administered 30 μg protein of BMSCs-exosomes or an equal volume of phosphate-buffered saline (PBS) via the retro-orbital route into C57BL/6 male mice 15 min after controlled cortical impact (CCI)-induced TBI. The results showed that the administration of BMSCs-exosomes reduced the lesion size and improved the neurobehavioral performance assessed by modified Neurological Severity Score (mNSS) and rotarod test. In addition, BMSCs-exosomes inhibited the expression of proapoptosis protein Bcl-2-associated X protein (BAX) and proinflammation cytokines, tumor necrosis factor-α (TNF-α) and interleukin (IL)-1β, while enhancing the expression of the anti-apoptosis protein B-cell lymphoma 2 (BCL-2). Furthermore, BMSCs-exosomes modulated microglia/macrophage polarization by downregulating the expression of inducible nitric oxide synthase (INOS) and upregulating the expression of clusters of differentiation 206 (CD206) and arginase-1 (Arg1). In summary, our result shows that BMSCs-exosomes serve a neuroprotective function by inhibiting early neuroinflammation in TBI mice through modulating the polarization of microglia/macrophages. Further research into this may serve as a potential therapeutic strategy for the future treatment of TBI

The international effort: building the bridge for Translational Medicine: Report of the 1st International Conference of Translational Medicine (ICTM)

Background: Supported by the International Society for Translational Medicine (ISTM), Wenzhou Medical College and the First Affiliated Hospital of Wenzhou Medical College, the International Conference on Translational Medicine (ICTM) was held on October 22–23, 2011 in Wenzhou, China. Nearly 800 registrants attended the meeting, primarily representing institutes and hospitals in Europe, The United States of America, And Asia, and China. The meeting was chaired and organized by Dr. Xiangdong Wang, Xiaoming Chen, Richard Coico, Jeffrey M. Drazen, Richard Horton, Francesco M. Marincola, Laurentiu M. Popescu, Jia Qu and Aamir Shahzad. Findings: The meeting focused on the communication of the need to foster translational medicine (TM) by building and broadening bridges between basic research and clinical studies at the international level. The meeting included distinguished TM experts from academia, the pharmaceutical and diagnostics industries, government agencies, regulators, and clinicians and provided the opportunity to identify shared interests and efforts for collaborative approaches utilizing cutting edge technologies, innovative approaches and novel therapeutic interventions. The meeting defined the concept of TM in its two-way operational scheme and emphasized the need for bed to bench efforts based directly on clinical observation. Conclusions: It was the meeting participants’ realization that the shared main goals of TM include breaking the separation between clinic practice and basic research, establishing positive feedback by understanding the basis of expected and unexpected clinical outcomes and accelerating basic research relevant to human suffering. The primary objectives of the meeting were two-fold: to accelerate the two-way translation by informing the participants representing the different disciplines about the state of art activities around TM approaches; and to identify areas that need to be supported by redirecting limited resources as well as identifying new sources of funding. This report summarizes key concepts presented during the meeting representing the state-of-art translational research and salient aspects of the ensuing discussions

Role for Neuronal Nitric Oxide Synthase in Cannabinoid-induced Neurogenesis

Abstract words: 240 Introduction words: 50