Microglial Activation, Agathisflavone and Neuroinflammation: Unveiling Promising Therapeutic Pathways


Neurodegenerative diseases, such as Alzheimer’s disease (AD), are characterized by the activation of microglia into a proinflammatory state, contributing significantly to neuroinflammation and subsequent neuronal damage. MicroRNAs (miRNAs), essential post-transcriptional regulators, play a pivotal role in modulating this inflammatory response. Recent studies have shed light on the potential of flavonoids, polyphenolic compounds found in various plant species, in mitigating neuroinflammation through miRNA-mediated pathways.

MiRNAs have emerged as crucial regulators in neurodegenerative diseases, including Alzheimer’s and Parkinson’s diseases. These endogenous RNA molecules exert their regulatory effects by binding to target mRNA, thereby modulating gene expression. Studies have implicated miRNAs in the regulation of the JAK2/STAT-3 signaling pathway, pivotal in mediating inflammatory responses in microglia. Notably, miR-155 has been associated with suppressing inflammatory cytokines by targeting p-STAT-3.

Conversely, microRNA-146a has been identified as a modulator of anxiety-like behavior, oxidative stress, and neuroinflammation. Zhao et al.’s study demonstrated the significant role of microRNA-146a in modulating these aspects in mice, highlighting its potential as a therapeutic target.

Flavonoids, known for their diverse biological effects including anti-inflammatory and antioxidant properties, have garnered attention for their neuroprotective potential. These compounds have been shown to modulate microglial activation and proinflammatory responses, potentially through miRNA-mediated mechanisms. Agathisflavone, a biflavonoid isolated from Cenostigma pyramidale leaves, has demonstrated neuroprotective and anti-neuroinflammatory properties. Previous research has linked its effects to the modulation of microglial inflammatory profiles, particularly in models of neuroinflammation and AD.

TABLE – The Neuroprotective Potential of Agathisflavone: Insights into Microglial Modulation

Agathisflavone, a biflavonoid extracted from the leaves of Cenostigma pyramidale, has garnered attention for its remarkable neuroprotective and anti-neuroinflammatory properties. Past investigations have elucidated its effects, particularly in modulating microglial inflammatory responses, offering promising prospects in combating neuroinflammation and neurodegenerative diseases such as Alzheimer’s disease (AD).

Microglia, the resident immune cells of the central nervous system (CNS), play a crucial role in maintaining CNS homeostasis. However, under pathological conditions like neuroinflammation and AD, microglia can undergo activation, leading to the release of inflammatory mediators and exacerbation of neuronal damage. Agathisflavone emerges as a potential therapeutic agent in modulating microglial activation and attenuating neuroinflammation.

Research has demonstrated the neuroprotective effects of agathisflavone, with evidence of its ability to mitigate neuronal damage and inflammation in various models of neurodegeneration. Its efficacy has been attributed to its modulation of microglial inflammatory profiles, thereby preserving CNS integrity and function.

Studies conducted in models of neuroinflammation and AD have provided compelling evidence supporting the anti-neuroinflammatory properties of agathisflavone. By regulating microglial activation and inflammatory mediator expression, agathisflavone shows promise in mitigating neuroinflammation, a hallmark feature of neurodegenerative diseases.

Furthermore, agathisflavone’s ability to downregulate the expression of inflammatory mediators, such as nitric oxide synthase 2 (NOS2) and proinflammatory cytokines, underscores its potential as a therapeutic agent in neuroinflammatory conditions. Its multifaceted mechanism of action involves modulation of signaling pathways, including the JAK2/STAT-3 pathway, implicated in inflammatory responses.

Importantly, agathisflavone’s neuroprotective effects extend beyond its anti-neuroinflammatory properties. Research suggests its involvement in preserving neuronal integrity and function, offering potential benefits in halting the progression of neurodegenerative diseases.

Agathisflavone emerges as a promising candidate for the treatment of neurodegenerative diseases, owing to its neuroprotective and anti-neuroinflammatory properties. Further elucidation of its mechanisms of action and clinical studies are warranted to harness its full therapeutic potential in combating neuroinflammation and preserving CNS function.

In this context, the role of flavonoids in regulating miRNAs and microglial activation is of particular interest. Agathisflavone has been implicated in modulating the neuroinflammatory response of human microglia through the regulation of miR-146a and miR-155. This finding underscores the potential of flavonoids as therapeutic agents in mitigating neuroinflammation associated with neurodegenerative diseases.

Overall, understanding the intricate interplay between microglial activation, miRNA regulation, and flavonoid-mediated neuroprotection provides valuable insights into novel therapeutic strategies for combating neurodegenerative diseases like Alzheimer’s. Further research elucidating the precise mechanisms underlying these interactions is warranted to harness the full therapeutic potential of flavonoids in the treatment of neurological disorders.

Discussion: Understanding the Dynamics of Microglial Activation and Flavonoid Intervention in Neuroinflammation

Microglia, the resident immune cells of the central nervous system (CNS), are pivotal in maintaining CNS homeostasis through immunological surveillance and interactions with neighboring cells. However, in conditions like neurodegenerative diseases, microglia undergo activation, leading to morphological alterations, proliferation, and release of inflammatory mediators, exacerbating CNS damage.

In the study, we investigated the impact of the biflavonoid agathisflavone on microglial inflammatory responses using a model of neuroinflammation induced by amyloid-beta (Aβ) and lipopolysaccharide (LPS) in human C20 microglia cultures. Our findings revealed that both Aβ and LPS triggered microglial activation, characterized by morphological changes and altered cytokine profiles, accompanied by an increase in microRNA-146a and microRNA-155 expression. Interestingly, treatment with agathisflavone mitigated microglial activation induced by Aβ and LPS, accompanied by a decrease in microRNA-146a and microRNA-155 levels.

Previously, our research demonstrated that agathisflavone effectively dampened microglial activation and reduced inflammatory mediator expression in rat microglia cultures exposed to LPS. Additionally, in cocultures of neurons and glial cells subjected to inflammatory damage, agathisflavone treatment led to neuroprotection and immunomodulation. These observations underscore the potential of flavonoids, particularly agathisflavone, in counteracting neuroinflammation by modulating microglial responses.

The activation of microglia involves complex stimuli and mechanisms, with emerging evidence implicating microRNAs (miRNAs) in this process. Alterations in miRNA regulation have been linked to the pathogenesis of neurodegenerative diseases and brain injuries. Notably, miRNAs such as miR-146a and miR-155 have been associated with the proinflammatory microglial phenotype, driving the expression of inflammatory cytokines and mediators.

TABLE 1 microRNAs

  • Activation of Microglia:
    • Microglia, as the resident immune cells of the central nervous system (CNS), play a crucial role in maintaining CNS homeostasis.
    • Upon encountering any insult or disturbance in the CNS, such as in neurodegenerative diseases or brain injuries, microglia undergo a process called activation.
    • Microglial activation involves a series of complex stimuli and mechanisms, which can vary depending on the nature and severity of the insult.
    • This activation process includes morphological changes, proliferation, migration, and the release of inflammatory mediators, such as cytokines and chemokines, which can exacerbate CNS damage if not properly regulated.
  • Role of MicroRNAs (miRNAs) in Microglial Activation:
    • Emerging evidence suggests that microRNAs (miRNAs), which are small RNA molecules involved in post-transcriptional gene regulation, play a significant role in microglial activation.
    • MiRNAs act as molecular switches, regulating the expression of genes involved in various cellular processes, including inflammation.
    • Alterations in miRNA regulation have been implicated in the pathogenesis of neurodegenerative diseases and brain injuries, indicating their crucial role in CNS health and disease.
    • Specifically, miRNAs such as miR-146a and miR-155 have garnered attention for their association with the proinflammatory microglial phenotype.
  • Association of miR-146a and miR-155 with Proinflammatory Microglial Phenotype:
    • MiR-146a and miR-155 have been identified as key regulators of the microglial inflammatory response.
    • These miRNAs are upregulated in activated microglia, particularly in the proinflammatory phenotype.
    • Their upregulation is associated with increased expression of inflammatory cytokines and mediators, such as interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), and nitric oxide synthase 2 (NOS2 or iNOS).
    • Consequently, miR-146a and miR-155 contribute to the amplification of the inflammatory response in the CNS, potentially exacerbating neuronal damage and neurodegeneration.
    • The dysregulation of these miRNAs has been implicated in the pathogenesis of various neurodegenerative diseases, highlighting their significance as potential therapeutic targets.

In summary, the activation of microglia involves a multifaceted process influenced by various stimuli and mechanisms. MiRNAs, particularly miR-146a and miR-155, play crucial roles in regulating the microglial inflammatory response and have been implicated in the pathogenesis of neurodegenerative diseases. Understanding the intricate interplay between miRNA regulation and microglial activation offers promising avenues for therapeutic intervention in neurological disorders.

Our study corroborates previous findings regarding the role of miR-146a and miR-155 in microglial activation. We observed upregulation of miR-146a and miR-155 in microglia exposed to Aβ and LPS, which was attenuated by agathisflavone treatment. This suggests that agathisflavone exerts its anti-neuroinflammatory effects partly through modulating miRNA expression in microglia.

Furthermore, we demonstrated that agathisflavone downregulated phosphorylated STAT-3 expression in inflamed microglia. The JAK/STAT signaling pathway, known for its involvement in inflammatory and autoimmune diseases, is closely linked to microglial activation. Agathisflavone’s inhibition of this pathway highlights its potential as a therapeutic agent in neuroinflammatory conditions.

In Alzheimer’s disease (AD), microglia recognize soluble Aβ oligomers through various cell surface receptors, triggering NF-κB activation and subsequent release of proinflammatory mediators. Agathisflavone, through its ability to negatively regulate NF-κB expression, shows promise in mitigating neuroinflammation associated with AD.

In conclusion, our study sheds light on the intricate interplay between microglial activation, miRNA regulation, and flavonoid intervention in neuroinflammation. Agathisflavone emerges as a potential therapeutic agent for mitigating neuroinflammation in neurodegenerative diseases, offering new avenues for therapeutic exploration.

reference link : https://www.mdpi.com/1422-0067/25/5/2547


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