Blocking Kv1.3 potassium channels prevents postoperative neuroinflammation and cognitive decline without impairing wound healing in mice

Lai, Ieng Kit; Valdearcos, Martín; Morioka, Kazuhito; Saxena, Sarah; Feng, Xiaomei; Li, Rong; Uchida, Yoshiyuki; Liu, An; Li, Wei; Pan, Jonathan Z.; Koliwad, Suneil K.; Marcucio, Ralph; Wulff, Heike; Maze, Mervyn

doi:10.1016/j.bja.2020.05.018

Cited by 26 publications

(29 citation statements)

References 53 publications

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“…The same study also reveals interestingly that PAP-1 does not affect peripheral IL-6 levels, confirming the central nervous system activity of PAP-1 (Ieng et al, 2020).…”

Section: Preventing Activation Of Microgliasupporting

confidence: 67%

“…Using a rodent model of aseptic trauma, we have investigated the potential role of microglia for cognitive decline assessed as a decrease in freezing behavior to a previously trained aversive stimulus. The putative pathogenic mechanisms responsible for the cognitive decline associated with the acute form of PND are illustrated in Figure 1 (Wan et al, 2007;Cibelli et al, 2010;Terrando et al, 2010Terrando et al, , 2011Degos et al, 2013;Vacas et al, 2014;Feng et al, 2017a,b;Hu et al, 2018a,b;Ieng et al, 2020).…”

Section: Role Of Microglia In Perioperative Neurocognitive Disorders (Pnd)mentioning

confidence: 99%

“…(A,B) Analyzed by one-way analysis of variance followed by Bonferroni post hoc test. (Ieng et al, 2020).…”

Section: Preventing Activation Of Microgliamentioning

confidence: 99%

“…FIGURE 4 | Phenoxyal koxypsoralen-1 (PAP-1) prevents surgery-induced hippocampal inflammation. Applied for Permission to Reproduce Ieng et al (2020). Mice with diet-induced obesity were randomized to four groups (n = 8 per group) that received either no surgery or surgery, and either PAP-1 or vehicle.…”

Section: Preventing Activation Of Microgliamentioning

confidence: 99%

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The Role of Microglia in Perioperative Neuroinflammation and Neurocognitive Disorders

Saxena

Kruys²,

Vamecq

et al. 2021

Front. Aging Neurosci.

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The aseptic trauma of peripheral surgery activates a systemic inflammatory response that results in neuro-inflammation; the microglia, the resident immunocompetent cells in the brain, are a key element of the neuroinflammatory response. In most settings microglia perform a surveillance role in the brain detecting and responding to “invaders” to maintain homeostasis. However, microglia have also been implicated in producing harm possibly by changing its phenotype from its beneficial, anti-inflammatory state (termed M2) into an injurious pro-inflammatory state (termed M1); it is likely that there are intermediates states between these polar phenotypes and some consider that a gradient exists with a number of intermediates, rather than a strict dichotomy between M1 and M2. In the pro-inflammatory phenotypes, microglia can disrupt synaptic plasticity such as long- term potentiation that can result in disorders of learning and memory of the type observed in Peri-operative Neurocognitive Disorders. Therefore, investigators have sought strategies to prevent microglia from provoking this adverse event in the perioperative period. In preclinical studies microglia can be depleted by removing trophic factors required for its maintenance; subsequent repopulation with a more beneficial microglial phenotype may result in memory enhancement, improved sensory motor function, as well as suppression of neuroinflammatory and oxidative stress pathways. Another approach consists of preventing microglial activation using the non-specific P38 MAP kinase blockers such as minocycline. Perhaps a more physiologic approach is the use of inhibitors of potassium (K+) channels that are required to convert the microglia into an active state. In this context the specific K+ channels that are implicated are termed Kv1.3 and KCa3.1 and high selective inhibitors for each have been developed. Data are accumulating demonstrating the utility of these K+ channel blockers in preventing Perioperative Neurocognitive Disorders.

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“…The same study also reveals interestingly that PAP-1 does not affect peripheral IL-6 levels, confirming the central nervous system activity of PAP-1 (Ieng et al, 2020).…”

Section: Preventing Activation Of Microgliasupporting

confidence: 67%

Section: Role Of Microglia In Perioperative Neurocognitive Disorders (Pnd)mentioning

confidence: 99%

“…(A,B) Analyzed by one-way analysis of variance followed by Bonferroni post hoc test. (Ieng et al, 2020).…”

Section: Preventing Activation Of Microgliamentioning

confidence: 99%

Section: Preventing Activation Of Microgliamentioning

confidence: 99%

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The Role of Microglia in Perioperative Neuroinflammation and Neurocognitive Disorders

Saxena

Kruys²,

Vamecq

et al. 2021

Front. Aging Neurosci.

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“…Similarly, in multiple animal models of Parkinson’s disease administration of the small molecule K V 1.3 blocker PAP-1 inhibited degeneration of dopaminergic neurons and improved behavioral outcomes [ 8 ]. K V 1.3 inhibition or genetic deletion has further been shown to ameliorate white matter pathology after traumatic brain injury [ 9 ], postoperative cognitive decline [ 10 ], and radiation induced brain injury [ 11 ]. In all these animal models of neurological disease increased K V 1.3 expression was observed on pathology-associated microglia and treatment with K V 1.3 blockers resulted in reduced microglia activation and reduced inflammatory cytokine levels in the brains of the animals.…”

Section: Introductionmentioning

confidence: 99%

Kv1.3 inhibition attenuates neuroinflammation through disruption of microglial calcium signaling

2020

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The potassium channel Kv1.3 as a therapeutic target for immunocytoprotection after reperfusion

Chen

Cui

Singh

et al. 2021

Ann Clin Transl Neurol

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Objective The voltage‐gated potassium channel Kv1.3, which is expressed on activated, disease‐associated microglia and memory T cells, constitutes an attractive target for immunocytoprotection after endovascular thrombectomy (EVT). Using young male mice and rats we previously demonstrated that the Kv1.3 blocker PAP‐1 when started 12 h after reperfusion dose‐dependently reduces infarction and improves neurological deficit on day 8. However, these proof‐of‐concept findings are of limited translational value because the majority of strokes occur in patients over 65 and, when considering overall lifetime risk, in females. Here, we therefore tested whether Kv1.3 deletion or delayed pharmacological therapy would be beneficial in females and aged animals. Methods Transient middle cerebral artery occlusion (tMCAO, 60 min) was induced in 16‐week‐old and 80‐week‐old male and female wild‐type C57BL/6J and Kv1.3−/− mice. Stroke outcomes were assessed daily with the 14‐score tactile and proprioceptive limp placing test and on day 8 before sacrifice by T2‐weighted MRI. Young and old female mice were treated twice daily with 40 mg/kg PAP‐1 starting 12 h after reperfusion. Microglia/macrophage activation and T‐cell infiltration were evaluated in whole slide scans. Results Kv1.3 deletion provided no significant benefit in young females but improved outcomes in young males, old males, and old females compared with wild‐type controls of the same sex. Delayed PAP‐1 treatment improved outcomes in both young and old females. In old females, Kv1.3 deletion and PAP‐1 treatment significantly reduced Iba‐1 and CD3 staining intensity in the ipsilateral hemisphere. Interpretation Our preclinical studies using aged and female mice further validate Kv1.3 inhibitors as potential adjunctive treatments for reperfusion therapy in stroke by providing both genetic and pharmacological verification.

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Blocking Kv1.3 potassium channels prevents postoperative neuroinflammation and cognitive decline without impairing wound healing in mice

Cited by 26 publications

References 53 publications

The Role of Microglia in Perioperative Neuroinflammation and Neurocognitive Disorders

The Role of Microglia in Perioperative Neuroinflammation and Neurocognitive Disorders

Kv1.3 inhibition attenuates neuroinflammation through disruption of microglial calcium signaling

The potassium channel Kv1.3 as a therapeutic target for immunocytoprotection after reperfusion

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