Inhibition of MK2 kinase as a potential therapeutic target to control neuroinflammation in Alzheimer’s disease

Srivastava, Shriyansh; Rajopadhye, Rohan; Dey, Mangaldeep; Singh, Rakesh Kumar

doi:10.1080/14728222.2021.1924151

Cited by 7 publications

(4 citation statements)

References 17 publications

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“…As depicted in Figure 3.3.3., p38β is expressed in both astrocytes and neurons suggesting that the p38-MAPK2 axis mediating inflammation post-AIS may be involved in both cell types. This is consistent with research that found the p38-MAPK2 axis is present and active in neurons (Beamer & Corrêa, 2021;Srivastava, Rajopadhye, Dey, & Singh, 2021). Furthermore, considering MAPK2 is mainly expressed in microglia and astrocytes (Beamer & Corrêa, 2021;Srivastava et al, 2021), there is a high probability that this signaling axis also occurs in glia.…”

Section: Impact Of Antidepressants On Il-1β Kir41 P38 and Pekr1/2 Exp...supporting

confidence: 91%

“…This is consistent with research that found the p38-MAPK2 axis is present and active in neurons (Beamer & Corrêa, 2021;Srivastava, Rajopadhye, Dey, & Singh, 2021). Furthermore, considering MAPK2 is mainly expressed in microglia and astrocytes (Beamer & Corrêa, 2021;Srivastava et al, 2021), there is a high probability that this signaling axis also occurs in glia. As well, this potential signaling pathway is more likely to involve p38β since this isoform is more abundantly expressed in astrocytes.…”

Section: Impact Of Antidepressants On Il-1β Kir41 P38 and Pekr1/2 Exp...supporting

confidence: 91%

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In vivo Analysis of kir4.1 Channel Expression Following Photothrombotic Stroke and Antidepressant Therapy

Milton¹

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Stroke is one of the leading causes of death and disability in Canada. Despite increasing morbidity rates, current stroke treatments are ineffective outside of a three-to six-hour window following symptom onset, indicating a critical need for alternative approaches to the management of symptoms. One such alternative is the use of antidepressant therapy to treat post-stroke depression (PSD). A pilot survey conducted for this dissertation found that Canadian hospitals and stroke centers frequently prescribe antidepressants following strokes. This survey also demonstrated that antidepressant treatment improved respondents, experience in two outcome domains (depression and anxiety or mood swings) and may have an impact on further deterioration in two specific domains (pain or numbness and inattention to one side of the body). The two antidepressants commonly used to treat PSD, fluoxetine and nortriptyline, have previously been shown to inhibit an inward rectifying potassium channel, known as kir4.1. Following a stroke, the kir4.1 channel has been shown to be responsible for the rapid reuptake of potassium to return the cell to baseline levels. This dissertation sought to examine the impact of inhibiting kir4.1 channel activity, using two common antidepressants (fluoxetine and nortriptyline), on proteins involved in astrocytic inflammation and cell survival post-stroke. The developmental expression pattern was first characterized as many developmental factors are known to play an important role in plasticity following traumatic brain injuries. The expression pattern of IL-1β, kir4.1, p38, and pERK1/2 following stroke were also evaluated; these four proteins were also examined following treatment with antidepressants (fluoxetine or nortriptyline).Four major conclusions were drawn from the animal studies. First, the level of kir4.1 expression fluctuated with development, with higher expression observed at E18 and P7 compared to older timepoints, and at P21 compared to aged adults. Second, significant cell death was seen iii at the 24-hour and three-day timepoints, followed by substantial cellular recovery by day seven post-stroke. Thirdly, an increase in IL-1β was found to coincide with reduced expression of the kir4.1, p38β and pERK1/2 expression in the first six hours after stroke. Only pERK1/2 remained reduced after six hours. Finally, nortriptyline was found to significantly increase kir4.1 and pERK1/2 expression, and significantly decrease p38β expression, when compared to the fluoxetine and saline conditions. Findings from the animal studies provide support for the idea that tricyclic antidepressants may be more appropriate in the preventative treatment of post-stroke depression (PSD). The clinical significance of these relationships remains unknown; however, both antidepressants appear to be prescribed to individuals who have recently suffered a stroke. Furthermore, it is likely that the kir4.1 channel is involved in the astrocytic response to antidepressants treatment in the prevention of PSD. iv Acknowledgement...

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Section: Impact Of Antidepressants On Il-1β Kir41 P38 and Pekr1/2 Exp...supporting

confidence: 91%

Section: Impact Of Antidepressants On Il-1β Kir41 P38 and Pekr1/2 Exp...supporting

confidence: 91%

In vivo Analysis of kir4.1 Channel Expression Following Photothrombotic Stroke and Antidepressant Therapy

Milton¹

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“…The CS exposure promotes microglia-induced activation of inflammation and oxidative stress leading to cytotoxicity through the TLR4-MAPK-activated protein kinase 2 (MAPKAPK2 or MK2) axis. It has been widely reported that MK2 kinase activation through the TLR4-induced P38MAPK pathway plays a key role in the pathology of Alzheimer's disease (Cha et al, 2023;Culbert et al, 2006;Srivastava et al, 2021). Although MK2 has been thought to regulate neuroinflammation and oxidative stress induced by amyloid beta (Aβ1-42), or lipopolysaccharide-exposed microglial cells and these responses were inhibited in MK2 knockout microglial cells (Culbert et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

MK2 inhibitor PF‐3644022 shows protective effect in mouse microglial N9 cell line induced with cigarette smoke extract

Asthana,

Pandey,

Gautam

et al. 2024

Chem Biol Drug Des

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Neuroinflammation is suggested as one of the potential links between CS‐induced neuronal dysfunction. Cigarette smoke (CS) is one of the significant contributors of neuroinflammation, consequently leading to cognitive impairment and neurodegeneration. Microglia are the key resident macrophage cells in the brain with cell surface TLR4 receptor for responding to various stress signals. The CS constituents promote inflammation and oxidative stress in microglia leading to cytotoxicity through the TLR4‐MK2 axis. However, the role of MK2 kinase in CS‐induced microglial inflammation is not yet clearly understood. Therefore, we have used an MK2 inhibitor, PF‐3644022 to study modulation of CS‐extract induced oxidative and inflammatory signaling in a mouse microglial cell line, Furthermore, we also evaluated the enzymatic activity of acetylcholinesterase (AChE) on a direct exposure of enzyme with CS. CS exposure led to microglial cytotoxicity and enhanced the level of oxidative stress and proinflammatory cytokine release by microglial cells. The microglial cells pretreated with MK2 inhibitor, PF‐3644022 significantly reduced the levels of oxidative stress markers, proinflammatory markers, and improved the level of antioxidant proteins in these cells. In addition, direct exposure of CS showed reduction in the enzymatic activity of AChE.

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“…AD represents the most common form of dementia with a high global burden and affects a global population of over 40 million, with a continuous increase of around 7.7 million new cases every year. [ 1,2 ] The two core pathophysiological hallmarks of AD include the deposition of amyloid‐β (Aβ) plaques and neurofibrillary tangles in the brain. [ 3,4 ] Despite extensive research on the mechanisms of production, deposition and the diverse approaches aimed at their prevention, there is still no effective drug to control these pathological hallmarks.…”

Section: Introductionmentioning

confidence: 99%

Exposure of aluminium to C6 glioma cells modulates molecular and functional neurotoxic markers

Dey

Singh

2022

J Biochem & Molecular Tox

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The risk of aluminium exposure to humans is very high as it may get into the human body through excessive dietary contaminants, inhalation of fine particulate matter, or through parenteral routes as a vaccine adjuvant and so forth. The increased level of aluminium in brain tissue has been shown to be associated with several neurodegenerative and neurotoxic adverse effects, including AD.However, the exact mechanism of aluminium-induced neurotoxicity is still unclear.Therefore, our study aimed to investigate the mechanism of neurotoxic and neurodegenerative effects through in vitro exposure of aluminium in rat glioma C6 cell line. The findings of our study have indicated that aluminium chloride exposure may lead to alteration in acetylcholine levels, increased oxidative imbalance and induction of molecular structural and functional markers of neuronal inflammation. This study also demonstrated that aluminium exposure may lead to the induction of caspase-3 along with apoptotic cell death and a significant increase in amyloid-beta and hyperphosphorylated tau levels in C6 cells. Thus, this study may provide a mechanistic understanding of the regulation of neuroinflammatory and neurodegenerative biomarkers due to aluminium exposure.

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Inhibition of MK2 kinase as a potential therapeutic target to control neuroinflammation in Alzheimer’s disease

Cited by 7 publications

References 17 publications

In vivo Analysis of kir4.1 Channel Expression Following Photothrombotic Stroke and Antidepressant Therapy

In vivo Analysis of kir4.1 Channel Expression Following Photothrombotic Stroke and Antidepressant Therapy

MK2 inhibitor PF‐3644022 shows protective effect in mouse microglial N9 cell line induced with cigarette smoke extract

Exposure of aluminium to C6 glioma cells modulates molecular and functional neurotoxic markers

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