Kv1.3 Channel as a Key Therapeutic Target for Neuroinflammatory Diseases: State of the Art and Beyond

Wang, Xiaoli; Li, Guoyi; Guo, Jingkang; Zhang, Zhiping; Zhang, Shuzhang; Zhu, Yudan; Cheng, Jiwei; Yu, Lu; Ji, Yonghua; Tao, Jie

doi:10.3389/fnins.2019.01393

Cited by 75 publications

(77 citation statements)

References 129 publications

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“… 9 , 10 The Kv1.3 channel was discovered in human T-cells, 11 was found to be highly expressed on inflammatory infiltrates in the MS brain, 12 and is expressed on macrophages, microglia, and effector memory T cells. 13 Selective and nonselective Kv1.3 channel blockers might thereby provide immunomodulatory properties by inhibiting cell proliferation and proinflammatory cytokine secretion. 14 Studies before 2009 failed to establish 4-AP as a symptomatic treatment for MS because drug blood levels in patients were unpredictable, with excessive doses being associated with the risk of epileptic seizures and impaired consciousness.…”

Section: -Aminopyridine In Neurologic Diseasementioning

confidence: 99%

Neuroprotective Properties of 4-Aminopyridine

Dietrich

Hartung

Albrecht

2021

Neurol Neuroimmunol Neuroinflamm

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As an antagonist of voltage-gated potassium (Kv) channels, 4-aminopyridine (4-AP) is used as symptomatic therapy in several neurologic disorders. The improvement of visual function and motor skills and relieve of fatigue in patients with MS have been attributed to 4-AP. Its prolonged release formulation (fampridine) has been approved for the symptomatic treatment of walking disability in MS. The beneficial effects were explained by the blockade of axonal Kv channels, thereby enhancing conduction along demyelinated axons. However, an increasing body of evidence suggests that 4-AP may have additional properties beyond the symptomatic mode of action. In this review, we summarize preclinical and clinical data on possible neuroprotective features of 4-AP.

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Section: -Aminopyridine In Neurologic Diseasementioning

confidence: 99%

Neuroprotective Properties of 4-Aminopyridine

Dietrich

Hartung

Albrecht

2021

Neurol Neuroimmunol Neuroinflamm

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“…Another interesting target is represented by the potassium channel Kv1.3. Its role in glial neuroinflammation and in the pathogenesis of nigrostriatal lesion of Parkinson's disease, multiple sclerosis, and Alzheimer's disease has recently been determined (Wang et al, 2020). To date, its role in the depressive spectrum complex is less clear.…”

Section: Introductionmentioning

confidence: 99%

The Emerging Role of SGK1 (Serum- and Glucocorticoid-Regulated Kinase 1) in Major Depressive Disorder: Hypothesis and Mechanisms

et al. 2020

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Major depressive disorder (MDD) is a heterogeneous psychiatric disease characterized by persistent low mood, diminished interests, and impaired cognitive and social functions. The multifactorial etiology of MDD is still largely unknown because of the complex genetic and environmental interactions involved. Therefore, no established mechanism can explain all the aspects of the disease. In this light, an extensive research about the pathophysiology of MDD has been carried out. Several pathogenic hypotheses, such as monoamines deficiency and neurobiological alterations in the stress-responsive system, including the hypothalamic-pituitary-adrenal (HPA) axis and the immune system, have been proposed for MDD. Over time, remarkable studies, mainly on preclinical rodent models, linked the serum-and glucocorticoid-regulated kinase 1 (SGK1) to the main features of MDD. SGK1 is a serine/threonine kinase belonging to the AGK Kinase family. SGK1 is ubiquitously expressed, which plays a pivotal role in the hormonal regulation of several ion channels, carriers, pumps, and transcription factors or regulators. SGK1 expression is modulated by cell stress and hormones, including gluco-and mineralocorticoids. Compelling evidence suggests that increased SGK1 expression or function is related to the pathogenic stress hypothesis of major depression. Therefore, the first part of the present review highlights the putative role of SGK1 as a critical mediator in the dysregulation of the HPA axis, observed under chronic stress conditions, and its controversial role in the neuroinflammation as well. The second part depicts the negative regulation exerted by SGK1 in the expression of both the brain-derived neurotrophic factor (BDNF) and the vascular endothelial growth factor (VEGF), resulting in an anti-neurogenic activity. Finally, the review focuses on the antidepressant-like effects of anti-oxidative nutraceuticals in several preclinical model of depression, resulting from the restoration of the physiological expression and/or activity of SGK1, which leads to an increase in neurogenesis. In summary, the purpose of this review is a systematic analysis of literature depicting SGK1 as molecular junction of the complex mechanisms underlying the MDD in an effort to suggest the kinase as a potential biomarker and strategic target in modern molecular antidepressant therapy.

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“…Although hundreds of bioactive compounds that have a potential drug lead were recorded recently from Cnidarian toxins, only one peptide (ShK-186) known as dalazatide has reached to the pharmaceutical market, passing every stage in the pathway of drug development (Liao et al 2018). This is used to treat autoimmune diseases, including neuroinflammatory diseases by targeting Kv1.3 channels (Wang et al 2020). This confirms the higher degree of success in bioprospecting the cnidarian neurotoxic peptide derivatives into treatments for neurological disorders.…”

Section: Bioactivities Of Cnidarian Toxinsmentioning

confidence: 56%

Cnidarian toxins: recent evidences for potential therapeutic uses

Jayathilake

Gunathilake

2020

The European Zoological Journal

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Marine toxins have received global attention for their involvement in human intoxication. Many marine phyla are well adapted to produce venoms or toxins protect themselves from associated micro fauna, predators and pathogens. Despite the toxicity, some bio toxins stand as potential drug leads in human and veterinary medicine. Amongst all marine fauna, Cnidarians are well renowned for producing bioactive peptides which are used in drug development, as they harbor various biological activities; anticancer, anti-inflammatory, immunomodulatory, radical scavenging, anti-parasitic activities, etc. Particularly, this review summarizes the bioactivities recorded from Cnidarian toxins and the possibility of using them as therapeutic agents, leading to develop into commercial products in the future.

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Kv1.3 Channel as a Key Therapeutic Target for Neuroinflammatory Diseases: State of the Art and Beyond

Cited by 75 publications

References 129 publications

Neuroprotective Properties of 4-Aminopyridine

Neuroprotective Properties of 4-Aminopyridine

The Emerging Role of SGK1 (Serum- and Glucocorticoid-Regulated Kinase 1) in Major Depressive Disorder: Hypothesis and Mechanisms

Cnidarian toxins: recent evidences for potential therapeutic uses

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