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Stroke is the fifth leading cause of death worldwide and is a main cause of disability in adults. Neither currently marketed drugs nor commonly used treatments can promote nerve repair and neurogenesis after stroke, and the repair of neurons damaged by ischemia has become a research focus. This article reviews several possible mechanisms of stroke...
Citations
... One such mechanism is the enhancement of growth factor release, including Brain-Derived Neurotrophic Factor (BDNF), Glial-Derived Neurotrophic Factor (GDNF), and Vascular Endothelial Growth Factor (VEGF) [20,21]. Growth factors such as BDNF improve stroke outcomes in preclinical studies and increase neurogenesis [22] but face therapeutic challenges due to their poor absorption, metabolic profile, and inability to easily cross the blood brain barrier [23]. In fact, several pleiotropic agents that are beneficial in preclinical stroke studies enhance BDNF production in the brain including estrogen [24], genistein [25], resveratrol [26], and metformin [27]. ...
Sigma 1 receptors are intracellular chaperone proteins that have been explored as a subacute treatment to enhance post-stroke recovery. We recently identified the antitussive oxeladin as a selective sigma 1 receptor agonist with the ability to stimulate the release of brain-derived neurotrophic factor from neurons in vitro. In this study, we hypothesized that oral oxeladin citrate would stimulate BDNF secretion and improve stroke outcomes when administered to male rats starting 48 h after transient middle cerebral artery occlusion. Oxeladin did not alter blood clotting and crossed the blood brain barrier within 30 min of oral administration. Rats underwent 90 min of transient middle cerebral artery occlusion. Forty-eight hours later rats began receiving daily oxeladin (135 mg/kg) for 11 days. Oxeladin significantly improved neurological function on days 3, 7, and 14 following MCAO. Infarct size was not altered by a single dose, but the final extent of infarct after 14 days was decreased. However, there was no significant reduction in astrogliosis or microgliosis compared to vehicle-treated control rats. In agreement with in vitro studies, oxeladin increased the amount of mature BDNF in the cerebral cortex 2, 6, and 24 h after single oral dose. However, the increase in BDNF did not result in increases in cellular proliferation in the subventricular zone or dentate gyrus when compared to vehicle-treated controls. These results suggest that oxeladin may reduce the extent of infarct expansion in the subacute phase of stroke, although this action does not appear to involve a reduction in inflammation or increased cell proliferation.
... Neurogenesis is known to be induced in infarcts and surrounding lesions in response to ischemic stroke [104]. Neural stem cells originating from the subventricular zone of the lateral ventricle and the dentate gyrus of the hippocampus [105] can be activated after ischemic stroke. ...
Ischemic stroke is a major cause of mortality and neurological morbidity worldwide. The underlying pathophysiology of ischemic stroke is highly complicated and correlates with various pathological processes, including neuroinflammation, oxidative stress injury, altered cell apoptosis and autophagy, excitotoxicity, and acidosis. The current treatment for ischemic stroke is limited to thrombolytic therapy such as recombinant tissue plasminogen activator. However, tissue plasminogen activator is limited by a very narrow therapeutic time window (<4.5 hours), selective efficacy, and hemorrhagic complication. Hence, the development of novel therapies to prevent ischemic damage to the brain is urgent. Chinese herbal medicine has a long history in treating stroke and its sequela. In the past decades, extensive studies have focused on the neuroprotective effects of Huanglian Jie Du decoction (HLJDD), an ancient and classical Chinese herbal formula that can treat a wide spectrum of disorders including ischemic stroke. In this review, the current evidence of HLJDD and its bioactive components for ischemic stroke is comprehensively reviewed, and their potential application directions in ischemic stroke management are discussed.
... 62,63 Upon activation, the phosphorylation level of p70S6K is obviously promoted, thus the development, differentiation, and regeneration of neurons could be reinforced. 64 Studies have shown that Zika virus infection of human fetal neural stem cells caused inhibition of the Akt/mTOR pathway, and impaired their proliferation and clonal expansion in neurospheres, leading to defective neurogenesis. 65 Gold nanoparticles have been reported to enhance the differentiation of embryonic stem cells into dopaminergic neurons via mTOR/ p70S6K pathway. ...
Ischemic stroke remains a leading cause of morbidity and disability around the world. The sequelae of serious neurological damage are irreversible due to body’s own limited repair capacity. However, endogenous neurogenesis induced by cerebral ischemia plays a critical role in the repair and regeneration of impaired neural cells after ischemic brain injury. mTOR (mammalian target of rapamycin) kinase has been suggested to regulate neural stem cells ability to self-renew and differentiate into proliferative daughter cells, thus leading to improved cell growth, proliferation, and survival. In this review, we summarized the current evidence to support that mTOR signaling pathways may enhance neurogenesis, angiogenesis, and synaptic plasticity following cerebral ischemia, which could highlight the potential of mTOR to be a viable therapeutic target for the treatment of ischemic brain injury.
... The activity of mTOR is regulated through phosphorylation on its specific residue serine 2448, which is the target of upstream Akt and downstream p70 ribosomal S6 kinase (p70S6K), and phosphorylation of threonine 389 residue by mTOR is critical for p70S6K activation and serves as a marker for mTOR activity (Chong et al., 2010;Chong et al., 2013). When AKT/mTOR pathway is activated, the phosphorylation level of downstream substrate p70S6K is remarkably upregulated, thus the development, differentiation, survival and regeneration of neurons as well as protein translation can be promoted (Li et al., 2020).To further explore potential mechanisms of enhanced neurogenesis in the hippocampal DG after PNS treatment, we next chose hippocampus tissue to examine the expression of Akt-mTOR-p70S6K signaling. Our western blot results have shown that the ratio of p-Akt/Akt, p-mTOR/mTOR, and p-p70S6K/p70S6K was obviously reduced after ME compared with sham group, however, PNS administration enhanced phosphorylation of Akt, mTOR, and p70S6K dosedependently after ME. ...
P. Notoginseng Saponins (PNS), the main active component of herbal medicine Panax notoginseng, has been widely used to treat cerebrovascular diseases. It has been acknowledged that PNS exerted protection on nerve injuries induced by ischemic stroke, however, the long-term impacts of PNS on the restoration of neurological defects and neuroregeneration after stroke have not been thoroughly studied and the underlying molecular mechanism of stimulating neurogenesis is difficult to precisely clarify, much more in-depth researches are badly needed. In the present study, cerebral ischemia injury was induced by microsphere embolism (ME) in rats. After 14 days, PNS administration relieved cerebral ischemia injury as evidenced by alleviating neurological deficits and reducing hippocampal pathological damage. What’s more, PNS stimulated hippocampal neurogenesis by promoting cell proliferation, migration and differentiation activity and modulated synaptic plasticity. Increased number of BrdU/Nestin, BrdU/DCX and NeuroD1-positive cells and upregulated synapse-related GAP43, SYP, and PSD95 expression were observed in the hippocampus. We hypothesized that upregulation of brain-derived neurotrophic factor (BDNF) expression and activation of Akt/mTOR/p70S6K signaling after ME could partially underlie the neuroprotective effects of PNS against cerebral ischemia injury. Our findings offer some new viewpoints into the beneficial roles of PNS against ischemic stroke.
... Cerebral ischemia (CI) is a widespread acute cerebrovascular disease, which is the second leading cause of death in the world, 1 and China has the highest burden of stroke in the world. 2 Ischemic stroke is characterized by high incidence rate, high disability rate and high mortality rate. 3,4 The critical aspect of treatment is to reduce or prevent the nerve injury caused by CI. 5,6 The neuroprotective effects of CI have been studied for more than half a century, especially in the past 30 years. 7,8 Nevertheless, the really effective method is still under exploration. ...
Background
Ketamine is famous for its dissociative anesthetic properties. It is also analgesic, anti-inflammatory and anti-depressant, and even has a cerebral protective effect. We searched the evidence of the correlation between ketamine target and clinical efficacy and utilized network pharmacology to gather information about the multi-target mechanism of ketamine against cerebral ischemia (CI). We found that ketamine’s clinical significance may be more extensive than previously thought.
Methods
The drug target of ketamine and CI-related genes were predicted by SwissTargetPrediction, DrugBank, PubChem, GeneCards and DisGeNET databases. The intersection of ketamine’s drug-targets and CI-related genes was analyzed by using GO and KEGG. We predicted the molecular docking between the potential target and ketamine.
Results
The results indicated that the effect of ketamine on CI was primarily associated with the target of α-synuclein (SNCA), muscarinic acetylcholine receptor M1 (CHRM1) and nitric oxide synthase 1 (NOS1). It principally regulates the signal pathways of circadian transmission, calcium signaling pathway, dopaminergic synapse, cholinergic synapse and glutamatergic synapse. Molecular docking analysis exhibited that hydrogen bond and Pi-Pi interaction were the predominant modes of interaction.
Conclusion
There are protein targets affected by ketamine in the treatment of CI. Three pivotal targets involving 298 proteins, SNCA, CHRM1 and NOS1, have emerged as multi-target mechanisms for ketamine in CI therapy. Similarly, this study also provides a new idea for introducing network pharmacology into the evaluation of multi-targeted drugs for CI and cerebral protection.
... The most-studied cellular model for hippocampal learning and memory is the detection of long term potential (LTP), which is a long lasting increase in the synaptic transmission efficiency induced by high frequency stimulation (12). Ischemic brain insults, whether caused by global or focal cerebral ischemia, may induce neurogenesis (13). Growth associated protein 43 (GAP43) is a membrane-bound protein that is located in the axonal growth cones of sprouting CNS axons (14); it has been extensively used to quantitate sprouting axons during neuroanatomical remodeling (15). ...
Hydroxyapatite (HA) has been extensively used as a reconstructive and prosthetic material for osseous tissue. The present study aimed to determine whether HA extract exerted effects on central nervous system injury following transient cerebral ischemia/reperfusion in rats. Male Wistar rats were treated with HA following bilateral common carotid artery clamping (two-vessel occlusion). The results demonstrated that treatment with HA extract attenuated the inhibition of long-term potential in a rat model of transient cerebral ischemia/reperfusion. Furthermore, HA extract improved axon regeneration, which was confirmed via the immunohistochemical analysis of growth associated protein 43 and glial fibrillary acidic protein. Taken together, the results of the present study provided preliminary evidence of the protective effect of HA on neuronal damage.
... In addition, transient forebrain ischemia increases pro-inflammatory cytokine release from astrocytes and microglia to enhance neuronal damage in the hippocampus [8,9]. Several mechanisms have been proposed for the execution of neuronal damage upon ischemic insult [10][11][12]; however, there is a dearth of therapeutic agents owing to their limited ability to cross the blood-brain barrier as well as the cell membrane. To overcome these difficulties, cell-penetrating peptides (CPPs) have been introduced [13], and one of these CPPs consists of the trans-acting activator of transcription (Tat), originating from the human immunodeficiency virus. ...
The present study explored the effects of endophilin A1 (SH3GL2) against oxidative damage brought about by H2O2 in HT22 cells and ischemic damage induced upon transient forebrain ischemia in gerbils. Tat-SH3GL2 and its control protein (Control-SH3GL2) were synthesized to deliver it to the cells by penetrating the cell membrane and blood–brain barrier. Tat-SH3GL2, but not Control-SH3GL2, could be delivered into HT22 cells in a concentration- and time-dependent manner and the hippocampus 8 h after treatment in gerbils. Tat-SH3GL2 was stably present in HT22 cells and degraded with time, by 36 h post treatment. Pre-incubation with Tat-SH3GL2, but not Control-SH3GL2, significantly ameliorated H2O2-induced cell death, DNA fragmentation, and reactive oxygen species formation. SH3GL2 immunoreactivity was decreased in the gerbil hippocampal CA1 region with time after ischemia, but it was maintained in the other regions after ischemia. Tat-SH3GL2 treatment in gerbils appreciably improved ischemia-induced hyperactivity 1 day after ischemia and the percentage of NeuN-immunoreactive surviving cells increased 4 days after ischemia. In addition, Tat-SH3GL2 treatment in gerbils alleviated the increase in lipid peroxidation as assessed by the levels of malondialdehyde and 8-iso-prostaglandin F2α and in pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin-1β, and interleukin-6; while the reduction of protein levels in markers for synaptic plasticity, such as postsynaptic density 95, synaptophysin, and synaptosome associated protein 25 after transient forebrain ischemia was also observed. These results suggest that Tat-SH3GL2 protects neurons from oxidative and ischemic damage by reducing lipid peroxidation and inflammation and improving synaptic plasticity after ischemia.
... [10,11] Elevated Bcl-2 expression is neuroprotective against apoptosis via the P13K/Akt pathway. [50] Providing 7-day acupuncture stimulation on GV-20 and GV-24 (Shenting) at 2 h after reperfusion, significantly increased the expression of beclin-1. In another case that started to apply stimulation on the same acupoints at 24 h after middle cerebral artery occlusion (MCAO), the mRNA expression of Bcl-2 mRNA was increased and beclin-1 was suppressed following 6 days of treatment. ...
... [17] Governor vessel meridian GV-20 (Baihui) promotes neurogenesis as well as triggers the proliferation and differentiation of vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF). [50,61] VEGF and BDNF are the vital neurotrophic factors in the survival signaling of neural stem cells (termed as astrocytes). Astrocytes not only function to initiate proliferation but also to promote tissue repair. ...
Context
Resveratrol (RV) is a natural compound found in grapes, wine, berries, and peanuts and has potential health benefits—namely, neurogenesis improvement. Neurogenesis, which is the process through which new neurons or nerve cells are generated in the brain, occurs in the subventricular zone and hippocampus and is influenced by various factors. RV has been shown to increase neural stem cell proliferation and survival, improving cognitive function in hippocampus-dependent tasks. Thus, to provide a convergent and unbiased conclusion of the available evidence on the correlation between the RV and neurogenesis, a systematic review needs to be undertaken meticulously and with appropriate attention.
Objective
This study aimed to systematically review any potential connection between the RV and neurogenesis in animal models.
Data Sources and Extraction
Based on the particular selection criteria, 8 original animal studies that investigated the relationship between RV and neurogenesis were included. Studies written in English and published in peer-reviewed journals with no restrictions on the starting date of publication on August 17, 2023, were searched in the Google Scholar and PubMed databases. Furthermore, data were extracted and analyzed independently by 2 researchers and then reviewed by a third researcher, and discrepancies were resolved by consensus. This project followed PRISMA reporting standards.
Data Analysis
In the studies analyzed in this review, there is a definite correlation between RV and neurogenesis, meaning that RV intake, irrespective of the mechanisms thereof, can boost neurogenesis in both the subventricular zone and hippocampus.
Conclusion
This finding, albeit with some limitations, provides a plausible indication of RV’s beneficial function in neurogenesis. Indeed, RV intake may result in neurogenesis benefits—namely, cognitive function, mood regulation, stress resilience, and neuroprotection, potentially preventing cognitive decline.
Background:
Stroke is the second leading cause of mortality and disability worldwide. Poststroke rehabilitation is still unsatisfactory in clinics, which brings great pain and economic burdens to stroke patients. In this study, an injectable hydrogel in which tannic acid (TA) acts as not only a building block but also a therapeutic drug, was developed for poststroke rehabilitation.
Methods:
TA is used as a building block to form an injectable hydrogel (TA gel) with carboxymethyl chitosan (CMCS) by multivalent hydrogen bonds. The morphology, rheological properties, and TA release behavior of the hydrogel were characterized. The abilities of the TA gel to modulate microglial (BV2 cells) polarization and subsequently enhance the neuroplasticity of neuro cells (N2a cells) were assessed in vitro. The TA gel was injected into the cavity of stroke mice to evaluate motor function recovery, microglial polarization, and neuroplasticity in vivo. The molecular pathway through which TA modulates microglial polarization was also explored both in vitro and in vivo.
Results:
The TA gel exhibited sustainable release behavior of TA. The TA gel can suppress the expression of CD16 and IL-1β, and upregulate the expression of CD206 and TGF-β in oxygen and glucose-deprived (OGD) BV2 cells, indicating the regulation of OGD BV2 cells to an anti-inflammatory phenotype in vitro. This finding further shows that the decrease in synaptophysin and PSD95 in OGD N2a cells is effectively recovered by anti-inflammatory BV2 cells. Furthermore, the TA gel decreased CD16/iNOS expression and increased CD206 expression in the peri-infarct area of stroke mice, implying anti-inflammatory polarization of microglia in vivo. The colocalization of PSD95 and Vglut1 stains, as well as Golgi staining, showed the enhancement of neuroplasticity by the TA gel. Spontaneously, the TA gel successfully recovered the motor function of stroke mice. The western blot results in vitro and in vivo suggested that the TA gel regulated microglial polarization via the NF-κB pathway.
Conclusion:
The TA gel serves as an effective brain injectable implant to treat stroke and shows promising potential to promote poststroke rehabilitation in the clinic.
