The Experts below are selected from a list of 20715 Experts worldwide ranked by ideXlab platform
Zhihua Yu - One of the best experts on this subject based on the ideXlab platform.
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The potassium channel KCa3.1 constitutes a Pharmacological Target for astrogliosis associated with ischemia stroke
Journal of Neuroinflammation, 2017Co-Authors: Mengni Yi, Xiaoling Gao, Herbert M Geller, Gaoxian Chen, Tianjiao Wei, Yanxia Wang, Hongzhuan Chen, Qin Lu, Zhihua YuAbstract:BackgroundReactive astrogliosis is one of the significantly pathological features in ischemic stroke accompanied with changes in gene expression, morphology, and proliferation. KCa3.1 was involved in TGF-β-induced astrogliosis in vitro and also contributed to astrogliosis-mediated neuroinflammation in neurodegeneration disease.MethodsWild type mice and KCa3.1−/− mice were subjected to permanent middle cerebral artery occlusion (pMCAO) to evaluate the infarct areas by 2,3,5-triphenyltetrazolium hydrochloride staining and neurological deficit. KCa3.1 channels expression and cell localization in the brain of pMCAO mice model were measured by immunoblotting and immunostaining. Glia activation and neuron loss was measured by immunostaining. DiBAC4 (3) and Fluo-4AM were used to measure membrane potential and cytosolic Ca2+ level in oxygen-glucose deprivation induced reactive astrocytes in vitro.ResultsImmunohistochemistry on pMCAO mice infarcts showed strong upregulation of KCa3.1 immunoreactivity in reactive astrogliosis. KCa3.1−/− mice exhibited significantly smaller infarct areas on pMCAO and improved neurological deficit. Both activated gliosis and neuronal loss were attenuated in KCa3.1−/− pMCAO mice. In the primary cultured astrocytes, the expressions of KCa3.1 and TRPV4 were increased associated with upregulation of astrogliosis marker GFAP induced by oxygen-glucose deprivation. The activation of KCa3.1 hyperpolarized membrane potential and, by promoting the driving force for calcium, induced calcium entry through TRPV4, a cation channel of the transient receptor potential family. Double-labeled staining showed that KCa3.1 and TRPV4 channels co-localized in astrocytes. Blockade of KCa3.1 or TRPV4 inhibited the phenotype switch of reactive astrogliosis.ConclusionsOur data suggested that KCa3.1 inhibition might represent a promising therapeutic strategy for ischemia stroke.
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the potassium channel kca3 1 constitutes a Pharmacological Target for astrogliosis associated with ischemia stroke
Journal of Neuroinflammation, 2017Co-Authors: Mengni Yi, Herbert M Geller, Gaoxian Chen, Yanxia Wang, Hongzhuan Chen, Qin Lu, Zhihua YuAbstract:Reactive astrogliosis is one of the significantly pathological features in ischemic stroke accompanied with changes in gene expression, morphology, and proliferation. KCa3.1 was involved in TGF-β-induced astrogliosis in vitro and also contributed to astrogliosis-mediated neuroinflammation in neurodegeneration disease. Wild type mice and KCa3.1−/− mice were subjected to permanent middle cerebral artery occlusion (pMCAO) to evaluate the infarct areas by 2,3,5-triphenyltetrazolium hydrochloride staining and neurological deficit. KCa3.1 channels expression and cell localization in the brain of pMCAO mice model were measured by immunoblotting and immunostaining. Glia activation and neuron loss was measured by immunostaining. DiBAC4 (3) and Fluo-4AM were used to measure membrane potential and cytosolic Ca2+ level in oxygen-glucose deprivation induced reactive astrocytes in vitro. Immunohistochemistry on pMCAO mice infarcts showed strong upregulation of KCa3.1 immunoreactivity in reactive astrogliosis. KCa3.1−/− mice exhibited significantly smaller infarct areas on pMCAO and improved neurological deficit. Both activated gliosis and neuronal loss were attenuated in KCa3.1−/− pMCAO mice. In the primary cultured astrocytes, the expressions of KCa3.1 and TRPV4 were increased associated with upregulation of astrogliosis marker GFAP induced by oxygen-glucose deprivation. The activation of KCa3.1 hyperpolarized membrane potential and, by promoting the driving force for calcium, induced calcium entry through TRPV4, a cation channel of the transient receptor potential family. Double-labeled staining showed that KCa3.1 and TRPV4 channels co-localized in astrocytes. Blockade of KCa3.1 or TRPV4 inhibited the phenotype switch of reactive astrogliosis. Our data suggested that KCa3.1 inhibition might represent a promising therapeutic strategy for ischemia stroke.
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kca3 1 constitutes a Pharmacological Target for astrogliosis associated with alzheimer s disease
Molecular and Cellular Neuroscience, 2016Co-Authors: Mengni Yi, Herbert M Geller, Zhihua Yu, Qin Lu, Panpan Yu, Hongzhuan ChenAbstract:Abstract Alzheimer's disease (AD) is the most common type of dementia and is characterized by a progression from decline of episodic memory to a global impairment of cognitive function. Astrogliosis is a hallmark feature of AD, and reactive gliosis has been considered as an important Target for intervention in various neurological disorders. We previously found in astrocyte cultures that the expression of the intermediate conductance calcium-activated potassium channel KCa3.1 was increased in reactive astrocytes induced by TGF-β, while Pharmacological blockade or genetic deletion of KCa3.1 attenuated astrogliosis. In this study, we sought to suppress reactive gliosis in the context of AD by inhibiting KCa3.1 and evaluate its effects on the cognitive impairment using murine animal models such as the senescence-accelerated mouse prone 8 (SAMP8) model that exhibits some AD-like symptoms. We found KCa3.1 expression was increased in reactive astrocytes as well as neurons in the brains of both SAMP8 mice and Alzheimer's disease patients. Blockade of KCa3.1 with the selective inhibitor TRAM-34 in SAMP8 mice resulted in a decrease in astrogliosis as well as microglia activation, and moreover an attenuation of memory deficits. Using KCa3.1 knockout mice, we further confirmed that deletion of KCa3.1 reduced the activation of astrocytes and microglia, and rescued the memory loss induced by intrahippocampal Aβ1–42 peptide injection. We also found in astrocyte cultures that blockade of KCa3.1 or deletion of KCa3.1 suppressed Aβ oligomer-induced astrogliosis. Our data suggest that KCa3.1 inhibition might represent a promising therapeutic strategy for AD treatment.
V. O. Tkachev - One of the best experts on this subject based on the ideXlab platform.
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keap1 nrf2 are redox sensitive signaling system as a Pharmacological Target
Biochemistry, 2013Co-Authors: N. K. Zenkov, E. B. Menshchikova, V. O. TkachevAbstract:The redox-sensitive signaling system Keap1/Nrf2/ARE plays a key role in maintenance of cellular homeostasis under stress, inflammatory, carcinogenic, and proapoptotic conditions, which allows us to consider it as a Pharmacological Target. Here we review the basic regulatory mechanisms of the Keap1/Nrf2/ARE system, key Targets for Pharmacological intervention, and interconnection of this system with other redox-sensitive transcriptional factors. We also discuss the range of currently available pharmaceuticals. Finally, we promote “indirect” antioxidants as a promising strategy for prevention and treatment of wide range of diseases associated with oxidative stress.
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Keap1/Nrf2/ARE redox-sensitive signaling system as a Pharmacological Target
Biochemistry (Moscow), 2013Co-Authors: N. K. Zenkov, E. B. Menshchikova, V. O. TkachevAbstract:The redox-sensitive signaling system Keap1/Nrf2/ARE plays a key role in maintenance of cellular homeostasis under stress, inflammatory, carcinogenic, and proapoptotic conditions, which allows us to consider it as a Pharmacological Target. Here we review the basic regulatory mechanisms of the Keap1/Nrf2/ARE system, key Targets for Pharmacological intervention, and interconnection of this system with other redox-sensitive transcriptional factors. We also discuss the range of currently available pharmaceuticals. Finally, we promote “indirect” antioxidants as a promising strategy for prevention and treatment of wide range of diseases associated with oxidative stress.
Umberto Spampinato - One of the best experts on this subject based on the ideXlab platform.
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Central serotonin2B receptor blockade inhibits cocaine-induced hyperlocomotion independently of changes of subcortical dopamine outflow
Neuropharmacology, 2015Co-Authors: Céline Devroye, Adeline Cathala, Barbara Di Marco, Filippo Caraci, Filippo Drago, Pier Vincenzo Piazza, Umberto SpampinatoAbstract:The central serotonin2B receptor (5-HT2BR) is currently considered as an interesting Pharmacological Target for improved treatment of drug addiction. In the present study, we assessed the effect of two selective 5-HT2BR antagonists, RS 127445 and LY 266097, on cocaine-induced hyperlocomotion and dopamine (DA) outflow in the nucleus accumbens (NAc) and the dorsal striatum of freely moving rats. The peripheral administration of RS 127445 (0.16 mg/kg, i.p.) or LY 266097 (0.63 mg/kg, i.p.) significantly reduced basal DA outflow in the NAc shell, but had no effect on cocaine (10 mg/kg, i.p.)-induced DA outflow in this brain region. Also, RS 127445 failed to modify both basal and cocaine-induced DA outflow in the NAc core and the dorsal striatum. Conversely, both 5-HT2BR antagonists reduced cocaine-induced hyperlocomotion. Furthermore, RS 127445 as well as the DA-R antagonist haloperidol (0.1 mg/kg, i.p.) reduced significantly the late-onset hyperlocomotion induced by the DA-R agonist quinpirole (0.5 mg/kg, s.c.). Altogether, these results demonstrate that 5-HT2BR blockade inhibits cocaine-induced hyperlocomotion independently of changes of subcortical DA outflow. This interaction takes place downstream to DA neurons and could involve an action at the level of dorsostriatal and/or NAc DA transmission, in keeping with the importance of these brain regions in the behavioural responses of cocaine. Overall, this study affords additional knowledge into the regulatory control exerted by the 5-HT2BR on ascending DA pathways, and provides additional support to the proposed role of 5-HT2BRs as a new Pharmacological Target in drug addiction.
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the central serotonin2b receptor a new Pharmacological Target to modulate the mesoaccumbens dopaminergic pathway activity
Journal of Neurochemistry, 2010Co-Authors: Agnes Auclair, Adeline Cathala, Pier Vincenzo Piazza, Frederic Sarrazin, Ronan Depoortere, Adrian Newmantancredi, Umberto SpampinatoAbstract:J. Neurochem. (2010) 114, 1323–1332. Abstract The function of the serotonin2B receptor (5-HT2BR) in the mammalian brain is poorly characterized, especially with regard to its influence on dopamine (DA) neuron activity. Here, we assessed this issue by evaluating effects of 5-HT2BRs ligands in the control of striatal and accumbal DA outflow, using in vivo microdialysis in halothane-anesthetized rats, and amphetamine-induced hyperlocomotion in vigil rats. The selective 5-HT2BR antagonist 1-[(2-chloro-3,4-dimethoxyphenyl)methyl]-2,3,4,9-tetrahydro-6-methyl-1H-pyrido[3,4-B]indole (LY 266097; 0.16 mg/kg, i.p.) had no influence on basal accumbal and striatal DA outflow but reduced significantly accumbal DA outflow when injected at 0.63 mg/kg. A significant reduction of basal DA outflow in the nucleus accumbens was also observed after i.p. administration of 0.16 mg/kg 2-amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine, another selective 5-HT2BR antagonist. In contrast, the 5-HT2BR agonist α-methyl-5-(2-thienylmethoxy)-1H-indole-3-ethanamine (3 mg/kg, s.c.) had no influence on basal DA outflow in either brain region. The increase in striatal and accumbal DA outflow induced by the 5-HT2CR inverse agonist 5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f] indole (5 mg/kg, i.p.) was unaltered by LY 266097 (0.63 mg/kg) pre-treatment. Conversely, LY 266097 (0.63 mg/kg) significantly diminished the increase in DA outflow induced by haloperidol (0.01 mg/kg, s.c.) or amphetamine (0.5 mg/kg, i.p.) in the nucleus accumbens, but not in the striatum. Amphetamine-induced hyperlocomotion (1 mg/kg) was also attenuated by LY 266097 (0.63 mg/kg). These findings demonstrate that 5-HT2BRs exert a facilitatory control on mesoaccumbens DA pathway activity, and suggest that they may constitute a new Target for improved treatment of DA-related neuropsychiatric disorders.
Gian Marco Leggio - One of the best experts on this subject based on the ideXlab platform.
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neurobiological links between depression and ad the role of tgf β1 signaling as a new Pharmacological Target
Pharmacological Research, 2018Co-Authors: Filippo Caraci, Simona Federica Spampinato, Maria Grazia Morgese, Fabio Tascedda, Maria Grazia Salluzzo, Maria Concetta Giambirtone, Giuseppe Caruso, Antonio Munafo, Sebastiano Alfio Torrisi, Gian Marco LeggioAbstract:Abstract In the last several years a large number of studies have demonstrated the neurobiological and clinical continuum between depression and Alzheimer’s disease (AD). Depression is a risk factor for the development of AD, and the presence of depressive symptoms significantly increases the conversion of Mild Cognitive Impairment (MCI) into AD. Common pathophysiological events have been identified in depression and AD, including neuroinflammation with an aberrant Tumor Necrosis Factor-α (TNF-α) signaling, and an impairment of Brain-Derived Neurotrophic Factor (BDNF) and Transforming-Growth-Factor-β1 (TGF-β1) signaling. TGF-β1 is an anti-inflammatory cytokine that exerts neuroprotective effects against amyloid-β (Aβ)-induced neurodegeneration, and it has a key role in memory formation and synaptic plasticity. TGF-β1 plasma levels are reduced in major depressed patients (MDD), correlate with depression severity, and significantly contribute to treatment resistance in MDD. The deficit of Smad-dependent TGF-β1 signaling is also an early event in AD pathogenesis, which contributes to inflammaging and cognitive decline in AD. A long-term treatment with antidepressants such as selective-serotonin-reuptake inhibitors (SSRIs) is known to reduce the risk of AD in patients with depression and, SSRIs, such as fluoxetine, increase the release of TGF-β1 from astrocytes and exert relevant neuroprotective effects in experimental models of AD. We propose the TGF-β1 signaling pathway as a common Pharmacological Target in depression and AD, and discuss the potential rescue of TGF-β1 signaling by antidepressants as a way to prevent the transition from depression to AD.
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dopamine d 3 receptor as a new Pharmacological Target for the treatment of depression
European Journal of Pharmacology, 2013Co-Authors: Gian Marco Leggio, Chiara Bianca Maria Platania, Filippo Caraci, Salvatore Salomone, Claudio Bucolo, Vincenzo Micale, Filippo DragoAbstract:A substantial proportion of depressed patients do not respond to current antidepressant drug therapies. So far, antidepressant drugs have been developed based on the "monoaminergic hypothesis" of depression, which considers a synaptic deficiency in 5-hydroxytryptamine (5-HT; serotonin) or noradrenaline as main cause. More recently, the dopaminergic system has been implicated in the efficacy of some antidepressants, such as desipramine, amineptine, nomifensine. Dysfunction of dopaminergic neurotransmission within the mesolimbic system may contribute to anhedonia, loss of motivation and psychomotor retardation in severe depressive disorders. Dopamine D-3 receptor subtype is located both pre- and postsynaptically in brain areas regulating motivation and reward-related behavior and has been implicated in depression-like behaviors. Activity of mesolimbic dopamine neurons in the reward circuit is a key determinant of behavioral susceptibility/resilience to chronic stress, which plays a central role in the pathogenesis of depression. Dopamine D-3 receptor expression and function are both down-regulated in stress and depression, and these changes are reversed by antidepressant treatments, suggesting that enhanced dopaminergic neurotransmission mediated by dopamine D-3 receptor participates in adaptive changes related to antidepressant activity. Of note, brain derived neurotrophic factor (BDNF) controls the expression of the dopamine 03 receptor in some brain areas and BEM induction by antidepressant treatments is related to their behavioral activity. A number of experimental drugs in pre-clinical or clinical development, including aripiprazole and cariprazine, may act as antidepressants because of their partial agonist activity at dopamine D-3 receptors. These preclinical and clinical data are discussed in the present review.
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Dopamine D3 receptor as a new Pharmacological Target for the treatment of depression
European Journal of Pharmacology, 2013Co-Authors: Gian Marco Leggio, Chiara Bianca Maria Platania, Filippo Caraci, Salvatore Salomone, Claudio Bucolo, Vincenzo Micale, Filippo DragoAbstract:A substantial proportion of depressed patients do not respond to current antidepressant drug therapies. So far, antidepressant drugs have been developed based on the "monoaminergic hypothesis" of depression, which considers a synaptic deficiency in 5-hydroxytryptamine (5-HT; serotonin) or noradrenaline as main cause. More recently, the dopaminergic system has been implicated in the efficacy of some antidepressants, such as desipramine, amineptine, nomifensine. Dysfunction of dopaminergic neurotransmission within the mesolimbic system may contribute to anhedonia, loss of motivation and psychomotor retardation in severe depressive disorders. Dopamine D3 receptor subtype is located both pre- and postsynaptically in brain areas regulating motivation and reward-related behavior and has been implicated in depression-like behaviors. Activity of mesolimbic dopamine neurons in the reward circuit is a key determinant of behavioral susceptibility/resilience to chronic stress, which plays a central role in the pathogenesis of depression. Dopamine D3 receptor expression and function are both down-regulated in stress and depression, and these changes are reversed by antidepressant treatments, suggesting that enhanced dopaminergic neurotransmission mediated by dopamine D3 receptor participates in adaptive changes related to antidepressant activity. Of note, brain derived neurotrophic factor (BDNF) controls the expression of the dopamine D3 receptor in some brain areas and BDNF induction by antidepressant treatments is related to their behavioral activity. A number of experimental drugs in pre-clinical or clinical development, including aripiprazole and cariprazine, may act as antidepressants because of their partial agonist activity at dopamine D3 receptors. These preclinical and clinical data are discussed in the present review. ?? 2013 Elsevier B.V.
Mengni Yi - One of the best experts on this subject based on the ideXlab platform.
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The potassium channel KCa3.1 constitutes a Pharmacological Target for astrogliosis associated with ischemia stroke
Journal of Neuroinflammation, 2017Co-Authors: Mengni Yi, Xiaoling Gao, Herbert M Geller, Gaoxian Chen, Tianjiao Wei, Yanxia Wang, Hongzhuan Chen, Qin Lu, Zhihua YuAbstract:BackgroundReactive astrogliosis is one of the significantly pathological features in ischemic stroke accompanied with changes in gene expression, morphology, and proliferation. KCa3.1 was involved in TGF-β-induced astrogliosis in vitro and also contributed to astrogliosis-mediated neuroinflammation in neurodegeneration disease.MethodsWild type mice and KCa3.1−/− mice were subjected to permanent middle cerebral artery occlusion (pMCAO) to evaluate the infarct areas by 2,3,5-triphenyltetrazolium hydrochloride staining and neurological deficit. KCa3.1 channels expression and cell localization in the brain of pMCAO mice model were measured by immunoblotting and immunostaining. Glia activation and neuron loss was measured by immunostaining. DiBAC4 (3) and Fluo-4AM were used to measure membrane potential and cytosolic Ca2+ level in oxygen-glucose deprivation induced reactive astrocytes in vitro.ResultsImmunohistochemistry on pMCAO mice infarcts showed strong upregulation of KCa3.1 immunoreactivity in reactive astrogliosis. KCa3.1−/− mice exhibited significantly smaller infarct areas on pMCAO and improved neurological deficit. Both activated gliosis and neuronal loss were attenuated in KCa3.1−/− pMCAO mice. In the primary cultured astrocytes, the expressions of KCa3.1 and TRPV4 were increased associated with upregulation of astrogliosis marker GFAP induced by oxygen-glucose deprivation. The activation of KCa3.1 hyperpolarized membrane potential and, by promoting the driving force for calcium, induced calcium entry through TRPV4, a cation channel of the transient receptor potential family. Double-labeled staining showed that KCa3.1 and TRPV4 channels co-localized in astrocytes. Blockade of KCa3.1 or TRPV4 inhibited the phenotype switch of reactive astrogliosis.ConclusionsOur data suggested that KCa3.1 inhibition might represent a promising therapeutic strategy for ischemia stroke.
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the potassium channel kca3 1 constitutes a Pharmacological Target for astrogliosis associated with ischemia stroke
Journal of Neuroinflammation, 2017Co-Authors: Mengni Yi, Herbert M Geller, Gaoxian Chen, Yanxia Wang, Hongzhuan Chen, Qin Lu, Zhihua YuAbstract:Reactive astrogliosis is one of the significantly pathological features in ischemic stroke accompanied with changes in gene expression, morphology, and proliferation. KCa3.1 was involved in TGF-β-induced astrogliosis in vitro and also contributed to astrogliosis-mediated neuroinflammation in neurodegeneration disease. Wild type mice and KCa3.1−/− mice were subjected to permanent middle cerebral artery occlusion (pMCAO) to evaluate the infarct areas by 2,3,5-triphenyltetrazolium hydrochloride staining and neurological deficit. KCa3.1 channels expression and cell localization in the brain of pMCAO mice model were measured by immunoblotting and immunostaining. Glia activation and neuron loss was measured by immunostaining. DiBAC4 (3) and Fluo-4AM were used to measure membrane potential and cytosolic Ca2+ level in oxygen-glucose deprivation induced reactive astrocytes in vitro. Immunohistochemistry on pMCAO mice infarcts showed strong upregulation of KCa3.1 immunoreactivity in reactive astrogliosis. KCa3.1−/− mice exhibited significantly smaller infarct areas on pMCAO and improved neurological deficit. Both activated gliosis and neuronal loss were attenuated in KCa3.1−/− pMCAO mice. In the primary cultured astrocytes, the expressions of KCa3.1 and TRPV4 were increased associated with upregulation of astrogliosis marker GFAP induced by oxygen-glucose deprivation. The activation of KCa3.1 hyperpolarized membrane potential and, by promoting the driving force for calcium, induced calcium entry through TRPV4, a cation channel of the transient receptor potential family. Double-labeled staining showed that KCa3.1 and TRPV4 channels co-localized in astrocytes. Blockade of KCa3.1 or TRPV4 inhibited the phenotype switch of reactive astrogliosis. Our data suggested that KCa3.1 inhibition might represent a promising therapeutic strategy for ischemia stroke.
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kca3 1 constitutes a Pharmacological Target for astrogliosis associated with alzheimer s disease
Molecular and Cellular Neuroscience, 2016Co-Authors: Mengni Yi, Herbert M Geller, Zhihua Yu, Qin Lu, Panpan Yu, Hongzhuan ChenAbstract:Abstract Alzheimer's disease (AD) is the most common type of dementia and is characterized by a progression from decline of episodic memory to a global impairment of cognitive function. Astrogliosis is a hallmark feature of AD, and reactive gliosis has been considered as an important Target for intervention in various neurological disorders. We previously found in astrocyte cultures that the expression of the intermediate conductance calcium-activated potassium channel KCa3.1 was increased in reactive astrocytes induced by TGF-β, while Pharmacological blockade or genetic deletion of KCa3.1 attenuated astrogliosis. In this study, we sought to suppress reactive gliosis in the context of AD by inhibiting KCa3.1 and evaluate its effects on the cognitive impairment using murine animal models such as the senescence-accelerated mouse prone 8 (SAMP8) model that exhibits some AD-like symptoms. We found KCa3.1 expression was increased in reactive astrocytes as well as neurons in the brains of both SAMP8 mice and Alzheimer's disease patients. Blockade of KCa3.1 with the selective inhibitor TRAM-34 in SAMP8 mice resulted in a decrease in astrogliosis as well as microglia activation, and moreover an attenuation of memory deficits. Using KCa3.1 knockout mice, we further confirmed that deletion of KCa3.1 reduced the activation of astrocytes and microglia, and rescued the memory loss induced by intrahippocampal Aβ1–42 peptide injection. We also found in astrocyte cultures that blockade of KCa3.1 or deletion of KCa3.1 suppressed Aβ oligomer-induced astrogliosis. Our data suggest that KCa3.1 inhibition might represent a promising therapeutic strategy for AD treatment.
