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  1. Article ; Online: Microglia as the Critical Regulators of Neuroprotection and Functional Recovery in Cerebral Ischemia.

    Gaire, Bhakta Prasad

    Cellular and molecular neurobiology

    2021  Volume 42, Issue 8, Page(s) 2505–2525

    Abstract: Microglial activation is considered as the critical pathogenic event in diverse central nervous system disorders including cerebral ischemia. Proinflammatory responses of activated microglia have been well reported in the ischemic brain and ... ...

    Abstract Microglial activation is considered as the critical pathogenic event in diverse central nervous system disorders including cerebral ischemia. Proinflammatory responses of activated microglia have been well reported in the ischemic brain and neuroinflammatory responses of activated microglia have been believed to be the potential therapeutic strategy. However, despite having proinflammatory roles, microglia can have significant anti-inflammatory roles and they are associated with the production of growth factors which are responsible for neuroprotection and recovery after ischemic injury. Microglia can directly promote neuroprotection by preventing ischemic infarct expansion and promoting functional outcomes. Indirectly, microglia are involved in promoting anti-inflammatory responses, neurogenesis, and angiogenesis in the ischemic brain which are crucial pathophysiological events for ischemic recovery. In fact, anti-inflammatory cytokines and growth factors produced by microglia can promote neuroprotection and attenuate neurobehavioral deficits. In addition, microglia regulate phagocytosis, axonal regeneration, blood-brain barrier protection, white matter integrity, and synaptic remodeling, which are essential for ischemic recovery. Microglia can also regulate crosstalk with neurons and other cell types to promote neuroprotection and ischemic recovery. This review mainly focuses on the roles of microglia in neuroprotection and recovery following ischemic injury. Furthermore, this review also sheds the light on the therapeutic potential of microglia in stroke patients.
    MeSH term(s) Anti-Inflammatory Agents/pharmacology ; Brain Ischemia/metabolism ; Cytokines/metabolism ; Humans ; Microglia/metabolism ; Neuroprotection
    Chemical Substances Anti-Inflammatory Agents ; Cytokines
    Language English
    Publishing date 2021-08-30
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 283404-2
    ISSN 1573-6830 ; 0272-4340
    ISSN (online) 1573-6830
    ISSN 0272-4340
    DOI 10.1007/s10571-021-01145-9
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  2. Article: Herbal Medicine in Ischemic Stroke: Challenges and Prospective.

    Gaire, Bhakta Prasad

    Chinese journal of integrative medicine

    2018  Volume 24, Issue 4, Page(s) 243–246

    Abstract: Herbal medicines, mainly of plant source, are invaluable source for the discovery of new therapeutic agents for all sorts of human ailments. The complex pathogenesis of stroke and multifactorial effect of herbal medicine and their active constituents may ...

    Abstract Herbal medicines, mainly of plant source, are invaluable source for the discovery of new therapeutic agents for all sorts of human ailments. The complex pathogenesis of stroke and multifactorial effect of herbal medicine and their active constituents may suggest the promising future of natural medicine for stroke treatment. Anti-oxidant, anti-inflammatory, anti-apoptotic, neuroprotective and vascular protective effect of herbal medicines are believed to be efficacious in stroke treatment. Herbs typically have fewer reported side effects than allopathic medicine, and may be safer to use over longer period of time. Herbal medicines are believed to be more effective for the longstanding health complaints, such as stroke. Several medicinal plants and their active constituents show the promising results in laboratory research. However failure in transformation of laboratory animal research to the clinical trials has created huge challenge for the use of herbal medicine in stroke. Until and unless scientifically comprehensive evidence of the efficacy and safety of herbal medicine in ischemic stroke patients is available, efforts should be made to continue implementing treatment strategies of proven effectiveness. More consideration should be paid to natural compounds that can have extensive therapeutic time windows, perfect pharmacological targets with few side effects. Herbal medicine has excellent prospective for the treatment of ischemic stroke, but a lot of effort should be invested to transform the success of animal research to human use.
    MeSH term(s) Animals ; Brain Ischemia/drug therapy ; Herbal Medicine ; Humans ; Neurons/pathology ; Neuroprotection ; Phytotherapy ; Stroke/drug therapy
    Language English
    Publishing date 2018-04-25
    Publishing country China
    Document type Journal Article ; Review
    ZDB-ID 2171254-2
    ISSN 1993-0402 ; 1672-0415
    ISSN (online) 1993-0402
    ISSN 1672-0415
    DOI 10.1007/s11655-018-2828-2
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    Zs.A 5823: Show issues Location:
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  3. Article ; Online: Critical Roles of Lysophospholipid Receptors in Activation of Neuroglia and Their Neuroinflammatory Responses.

    Gaire, Bhakta Prasad / Choi, Ji-Woong

    International journal of molecular sciences

    2021  Volume 22, Issue 15

    Abstract: Activation of microglia and/or astrocytes often releases proinflammatory molecules as critical pathogenic mediators that can promote neuroinflammation and secondary brain damages in diverse diseases of the central nervous system (CNS). Therefore, ... ...

    Abstract Activation of microglia and/or astrocytes often releases proinflammatory molecules as critical pathogenic mediators that can promote neuroinflammation and secondary brain damages in diverse diseases of the central nervous system (CNS). Therefore, controlling the activation of glial cells and their neuroinflammatory responses has been considered as a potential therapeutic strategy for treating neuroinflammatory diseases. Recently, receptor-mediated lysophospholipid signaling, sphingosine 1-phosphate (S1P) receptor- and lysophosphatidic acid (LPA) receptor-mediated signaling in particular, has drawn scientific interest because of its critical roles in pathogenies of diverse neurological diseases such as neuropathic pain, systemic sclerosis, spinal cord injury, multiple sclerosis, cerebral ischemia, traumatic brain injury, hypoxia, hydrocephalus, and neuropsychiatric disorders. Activation of microglia and/or astrocytes is a common pathogenic event shared by most of these CNS disorders, indicating that lysophospholipid receptors could influence glial activation. In fact, many studies have reported that several S1P and LPA receptors can influence glial activation during the pathogenesis of cerebral ischemia and multiple sclerosis. This review aims to provide a comprehensive framework about the roles of S1P and LPA receptors in the activation of microglia and/or astrocytes and their neuroinflammatory responses in CNS diseases.
    MeSH term(s) Animals ; Astrocytes/metabolism ; Central Nervous System Diseases/metabolism ; Humans ; Neuroglia/metabolism ; Receptors, Lysophosphatidic Acid/metabolism ; Sphingosine-1-Phosphate Receptors/metabolism
    Chemical Substances Receptors, Lysophosphatidic Acid ; Sphingosine-1-Phosphate Receptors
    Language English
    Publishing date 2021-07-23
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms22157864
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  4. Article ; Online: Neuroprotective Effects of Curcumin in Cerebral Ischemia: Cellular and Molecular Mechanisms.

    Subedi, Lalita / Gaire, Bhakta Prasad

    ACS chemical neuroscience

    2021  Volume 12, Issue 14, Page(s) 2562–2572

    Abstract: Despite being a major global health concern, cerebral ischemia/stroke has limited therapeutic options. Tissue plasminogen activator (tPA) is the only available medication to manage acute ischemic stroke, but this medication is associated with adverse ... ...

    Abstract Despite being a major global health concern, cerebral ischemia/stroke has limited therapeutic options. Tissue plasminogen activator (tPA) is the only available medication to manage acute ischemic stroke, but this medication is associated with adverse effects and has a narrow therapeutic time window. Curcumin, a polyphenol that is abundantly present in the rhizome of the turmeric plant (
    MeSH term(s) Animals ; Brain Ischemia/drug therapy ; Curcumin/pharmacology ; Neuroprotective Agents/pharmacology ; Stroke/drug therapy ; Tissue Plasminogen Activator
    Chemical Substances Neuroprotective Agents ; Tissue Plasminogen Activator (EC 3.4.21.68) ; Curcumin (IT942ZTH98)
    Language English
    Publishing date 2021-07-12
    Publishing country United States
    Document type Journal Article ; Review
    ISSN 1948-7193
    ISSN (online) 1948-7193
    DOI 10.1021/acschemneuro.1c00153
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  5. Article ; Online: Phytochemicals as regulators of microglia/macrophages activation in cerebral ischemia.

    Subedi, Lalita / Gaire, Bhakta Prasad

    Pharmacological research

    2021  Volume 165, Page(s) 105419

    Abstract: The search for novel therapeutic agents for the management of cerebral ischemia/stroke has become an appealing research interest in the recent past. Neuroprotective phytochemicals as novel stroke drug candidates have recently drawn significant interests ... ...

    Abstract The search for novel therapeutic agents for the management of cerebral ischemia/stroke has become an appealing research interest in the recent past. Neuroprotective phytochemicals as novel stroke drug candidates have recently drawn significant interests from stroke scientists due to their strong brain protective effects in animal stroke models. The underlying mechanism of action is likely owing to their anti-inflammatory properties, even though other mechanisms such as anti-oxidation and vasculoprotection have also been proposed. It is generally held that the early proinflammatory responses after stroke can lead to a secondary brain injury, mainly due to the damaging effect exerted by over-activation of brain resident microglial cells and infiltration of circulating monocytes and macrophages. This review focuses on the anti-inflammatory properties of bioactive phytochemicals, including activation and polarization of microglia/macrophages in the post-ischemic brain. The latest studies in animal stroke models demonstrate that this group of bioactive phytochemicals exerts their anti-inflammatory effects via attenuation of brain proinflammatory microglia and macrophages M1 polarization while promoting anti-inflammatory microglial and macrophages M2 polarization. As a result, stroked animals treated with brain protective phytochemicals have significantly fewer brain active M1 microglia and macrophages, smaller brain infarct volume, better functional recovery, and better survival rate. Therefore, this review provides insights into a new category of drug candidates for stroke drug development by employing neuroprotective phytochemicals.
    MeSH term(s) Animals ; Brain Ischemia/drug therapy ; Humans ; Macrophage Activation/drug effects ; Macrophages/drug effects ; Microglia/drug effects ; Neuroinflammatory Diseases/drug therapy ; Neuroprotective Agents/therapeutic use ; Phytochemicals/therapeutic use
    Chemical Substances Neuroprotective Agents ; Phytochemicals
    Language English
    Publishing date 2021-01-12
    Publishing country Netherlands
    Document type Journal Article ; Review
    ZDB-ID 1003347-6
    ISSN 1096-1186 ; 0031-6989 ; 1043-6618
    ISSN (online) 1096-1186
    ISSN 0031-6989 ; 1043-6618
    DOI 10.1016/j.phrs.2021.105419
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    Zs.A 721: Show issues Location:
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  6. Article ; Online: Tanshinone IIA: A phytochemical as a promising drug candidate for neurodegenerative diseases.

    Subedi, Lalita / Gaire, Bhakta Prasad

    Pharmacological research

    2021  Volume 169, Page(s) 105661

    Abstract: Tanshinones, lipophilic diterpenes isolated from the rhizome of Salvia miltiorrhiza, have diverse pharmacological activities against human ailments including neurological diseases. In fact, tanshinones have been used to treat heart diseases, stroke, and ... ...

    Abstract Tanshinones, lipophilic diterpenes isolated from the rhizome of Salvia miltiorrhiza, have diverse pharmacological activities against human ailments including neurological diseases. In fact, tanshinones have been used to treat heart diseases, stroke, and vascular diseases in traditional Chinese medicine. During the last decade, tanshinones have been the most widely studied phytochemicals for their neuroprotective effects against experimental models of cerebral ischemia and Alzheimer's diseases. Importantly, tanshinone IIA, mostly studied tanshinone for biological activities, is recently reported to attenuate blood-brain barrier permeability among stroke patients, suggesting tanshinone IIA as an appealing therapeutic candidate for neurological diseases. Tanshinone I and IIA are also effective in experimental models of Parkinson's disease, Multiple sclerosis, and other neuroinflammatory diseases. In addition, several experimental studies suggested the pleiotropic neuroprotective effects of tanshinones such as anti-inflammatory, antioxidant, anti-apoptotic, and BBB protectant further value aiding to tanshinone as an appealing therapeutic strategy in neurological diseases. Therefore, in this review, we aimed to compile the recent updates and cellular and molecular mechanisms of neuroprotection of tanshinone IIA in diverse neurological diseases.
    MeSH term(s) Abietanes/therapeutic use ; Alzheimer Disease/drug therapy ; Animals ; Brain Ischemia/drug therapy ; Humans ; Multiple Sclerosis/drug therapy ; Neurodegenerative Diseases/drug therapy ; Neuroprotective Agents/therapeutic use ; Parkinson Disease/drug therapy
    Chemical Substances Abietanes ; Neuroprotective Agents ; tanshinone (03UUH3J385)
    Language English
    Publishing date 2021-05-07
    Publishing country Netherlands
    Document type Journal Article ; Review
    ZDB-ID 1003347-6
    ISSN 1096-1186 ; 0031-6989 ; 1043-6618
    ISSN (online) 1096-1186
    ISSN 0031-6989 ; 1043-6618
    DOI 10.1016/j.phrs.2021.105661
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  7. Article ; Online: Sphingosine 1-Phosphate Receptors in Cerebral Ischemia.

    Gaire, Bhakta Prasad / Choi, Ji Woong

    Neuromolecular medicine

    2020  Volume 23, Issue 1, Page(s) 211–223

    Abstract: Sphingosine 1-phosphate (S1P) is an important lipid biomolecule that exerts pleiotropic cellular actions as it binds to and activates its five G-protein-coupled receptors, ... ...

    Abstract Sphingosine 1-phosphate (S1P) is an important lipid biomolecule that exerts pleiotropic cellular actions as it binds to and activates its five G-protein-coupled receptors, S1P
    MeSH term(s) Animals ; Brain Damage, Chronic/etiology ; Brain Damage, Chronic/metabolism ; Brain Ischemia/complications ; Brain Ischemia/metabolism ; Clinical Trials as Topic ; Disease Models, Animal ; Drug Evaluation, Preclinical ; Fingolimod Hydrochloride/therapeutic use ; Humans ; Infarction, Middle Cerebral Artery/drug therapy ; Infarction, Middle Cerebral Artery/metabolism ; Inflammation ; Ischemic Stroke/drug therapy ; Lysophospholipids/physiology ; Neovascularization, Physiologic/drug effects ; Nerve Tissue Proteins/physiology ; Neuroprotective Agents/therapeutic use ; Phosphotransferases (Alcohol Group Acceptor)/physiology ; Rats ; Signal Transduction/physiology ; Sphingosine/analogs & derivatives ; Sphingosine/physiology ; Sphingosine-1-Phosphate Receptors/physiology
    Chemical Substances Lysophospholipids ; Nerve Tissue Proteins ; Neuroprotective Agents ; Sphingosine-1-Phosphate Receptors ; sphingosine 1-phosphate (26993-30-6) ; Phosphotransferases (Alcohol Group Acceptor) (EC 2.7.1.-) ; sphingosine kinase (EC 2.7.1.-) ; Fingolimod Hydrochloride (G926EC510T) ; Sphingosine (NGZ37HRE42)
    Language English
    Publishing date 2020-09-10
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2077809-0
    ISSN 1559-1174 ; 1535-1084
    ISSN (online) 1559-1174
    ISSN 1535-1084
    DOI 10.1007/s12017-020-08614-2
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  8. Article ; Online: Sphingosine kinase 2 as the promising target for stroke research.

    Gaire, Bhakta Prasad

    International journal of stroke : official journal of the International Stroke Society

    2016  Volume 13, Issue 4, Page(s) NP11–NP12

    MeSH term(s) Adaptor Proteins, Signal Transducing/physiology ; Brain Ischemia/enzymology ; Humans ; Phosphotransferases (Alcohol Group Acceptor)/physiology ; Stroke/enzymology
    Chemical Substances Adaptor Proteins, Signal Transducing ; SPHKAP protein, human ; Phosphotransferases (Alcohol Group Acceptor) (EC 2.7.1.-) ; sphingosine kinase 2, human (EC 2.7.1.91)
    Language English
    Publishing date 2016-01-05
    Publishing country United States
    Document type Letter
    ZDB-ID 2303728-3
    ISSN 1747-4949 ; 1747-4930
    ISSN (online) 1747-4949
    ISSN 1747-4930
    DOI 10.1177/1747493015611316
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    Zs.A 6582: Show issues Location:
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  9. Article: BMS-986020, a Specific LPA1 Antagonist, Provides Neuroprotection against Ischemic Stroke in Mice

    Gaire, Bhakta Prasad / Sapkota, Arjun / Choi, Ji Woong

    Antioxidants. 2020 Nov. 08, v. 9, no. 11

    2020  

    Abstract: Stroke is a leading cause of death. Stroke survivors often suffer from long-term functional disability. This study demonstrated neuroprotective effects of BMS-986020 (BMS), a selective lysophosphatidic acid receptor 1 (LPA₁) antagonist under clinical ... ...

    Abstract Stroke is a leading cause of death. Stroke survivors often suffer from long-term functional disability. This study demonstrated neuroprotective effects of BMS-986020 (BMS), a selective lysophosphatidic acid receptor 1 (LPA₁) antagonist under clinical trials for lung fibrosis and psoriasis, against both acute and sub-acute injuries after ischemic stroke by employing a mouse model with transient middle cerebral artery occlusion (tMCAO). BMS administration immediately after reperfusion significantly attenuated acute brain injuries including brain infarction, neurological deficits, and cell apoptosis at day 1 after tMCAO. Neuroprotective effects of BMS were preserved even when administered at 3 h after reperfusion. Neuroprotection by BMS against acute injuries was associated with attenuation of microglial activation and lipid peroxidation in post-ischemic brains. Notably, repeated BMS administration daily for 14 days after tMCAO exerted long-term neuroprotection in tMCAO-challenged mice, as evidenced by significantly attenuated neurological deficits and improved survival rate. It also attenuated brain tissue loss and cell apoptosis in post-ischemic brains. Mechanistically, it significantly enhanced neurogenesis and angiogenesis in injured brains. A single administration of BMS provided similar long-term neuroprotection except survival rate. Collectively, BMS provided neuroprotection against both acute and sub-acute injuries of ischemic stroke, indicating that BMS might be an appealing therapeutic agent to treat ischemic stroke.
    Keywords angiogenesis ; antagonists ; antioxidants ; apoptosis ; brain ; brain damage ; clinical trials ; death ; fibrosis ; infarction ; lipid peroxidation ; lungs ; mice ; neurogenesis ; neuroprotective effect ; psoriasis ; stroke ; survival rate ; therapeutics
    Language English
    Dates of publication 2020-1108
    Publishing place Multidisciplinary Digital Publishing Institute
    Document type Article
    Note NAL-light
    ZDB-ID 2704216-9
    ISSN 2076-3921
    ISSN 2076-3921
    DOI 10.3390/antiox9111097
    Database NAL-Catalogue (AGRICOLA)

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  10. Article: BMS-986020, a Specific LPA

    Gaire, Bhakta Prasad / Sapkota, Arjun / Choi, Ji Woong

    Antioxidants (Basel, Switzerland)

    2020  Volume 9, Issue 11

    Abstract: Stroke is a leading cause of death. Stroke survivors often suffer from long-term functional disability. This study demonstrated neuroprotective effects of BMS-986020 (BMS), a selective lysophosphatidic acid receptor 1 ( ... ...

    Abstract Stroke is a leading cause of death. Stroke survivors often suffer from long-term functional disability. This study demonstrated neuroprotective effects of BMS-986020 (BMS), a selective lysophosphatidic acid receptor 1 (LPA
    Language English
    Publishing date 2020-11-08
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2704216-9
    ISSN 2076-3921
    ISSN 2076-3921
    DOI 10.3390/antiox9111097
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