Suppression of Lipopolysaccharide-Induced Neuroinflammation by Morin via MAPK, PI3K/Akt, and PKA/HO-1 Signaling Pathway Modulation

Abstract

Morin is a flavonoid isolated from certain fruits and Chinese herbs and is known to possess various medicinal properties. In this study, we investigated the anti-inflammatory effects of morin on lipopolysaccharide (LPS)-induced microglial activation, both in vitro and in vivo. We found that morin inhibited inducible nitric oxide synthase (iNOS) and pro-inflammatory cytokines in LPS-stimulated BV2 microglial cells. Furthermore, morin suppressed the microglial activation and cytokine expression in the brains of LPS-stimulated mice. Subsequent mechanistic studies revealed that morin inhibited the action of LPS-activated mitogen-activated protein kinases (MAPKs), protein kinase B (Akt) phosphorylation, nuclear factor-κB (NF-κB), and activating protein-1 (AP-1). Further, the phosphorylation and DNA binding activity of cAMP responsive element binding protein (CREB) was enhanced by morin. Moreover, morin suppressed the LPS-induced expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits, while it increased heme oxygenase-1 (HO-1) expression and nuclear factor erythroid 2-related factor 2 (Nrf2) activation. Therefore, our data suggest that morin exerts anti-inflammatory effects in LPS-stimulated microglia by downregulating MAPK and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways while upregulating protein kinase A (PKA)/CREB and Nrf2/HO-1 signaling pathways.

Microglia Mediated Neuroinflammation: Focus on PI3K Modulation

“…A number of in vitro models, including microglia cell lines, stem cell derived microglia cultures, and primary dissociated cell cultures, were performed in order to study the role of microglia in neurodegenerative disorders and, in particular, relevant to PI3K signaling (for more detail, see [73]). This anti-inflammatory beneficial effect could be linked to the ability of inhibiting PI3K/Akt signaling pathways [74,75].…”

“…Morin, a flavonoid, exerts anti-inflammatory effects by downregulating MAPK and PI3K/Akt signaling pathways and upregulating the anti-inflammatory PKA/CREB and Nrf2/HO-1 pathways in microglia [75]. Furthermore, TGF-1α, an anti-inflammatory molecule, protects brain by repressing the overactivation of microglial cells via inhibition of PI3K and its downstream signaling molecules [123].…”

Involvement of l‐arginine‐nitric oxide pathway in the antidepressant and memory promoting effects of morin in mice

“…Our finding showed that pretreatment with methylene blue at a subeffective, abolished the effect of morin on locomotion. Although we cannot completely rule out the possibility that other isoforms of NO synthase‐dependent mechanisms may underlie the psychotropic effect of morin (Ben‐Azu et al, 2019; Jung et al, ), this finding further implicates the role of l ‐arginine‐NO pathways and also suggests that nNOS isoform is involved in the effect of morin. Together, this finding and other investigations confirm that modulation of the neuronal isoform of NOS is critical for the central effects of NOS inhibitors on locomotion (Haj‐Mirzaian et al, ; Vale, Green, Montgomery, & Shafi, ; Volke et al, ).…”

“…Morin is a neuroactive polyphenolic compound obtained from mulberry leaves (Kapoor & Kakkar, ). Previous preclinical investigations have reported that morin demonstrated immunomodulatory and antineuroinflammatory (Jung et al, ; Ola et al, ), antioxidant (Ola et al, ), antidiabetic (Ola et al, ), antixanthine (Yu, Fong, & Cheng, ), antihypertensive (Prahalathan, Saravanakumar, & Raja, ), and anticancer (Zhang et al, ) properties. Recent studies have also shown that morin produces antidepressant (Ben‐Azu et al, ), antipsychotic (Ben‐Azu, Aderibigbe, Omogbiya, Ajayi, & Iwalewa, ; Ben‐Azu et al, ; Ben‐Azu, Aderibigbe, Eneni, et al, ; Ben‐Azu et al, ), anxiolytic (Mangaiarkkarasi, Viswanathan, Ramaswamy, & Tharani, ), antiamnesic (Lemkul & Bevan, ), and anti‐Parkinsonia (Zhang et al, ) properties in behavioral paradigms.…”

“…Morin also decreases loss of cortical pyramidal via inhibition of neuroinflammation and nitrergic stress in a two‐hit mouse model of schizophrenia (Ben‐Azu et al, 2019). Moreover, morin suppressed upregulation of inducible nitric oxide synthase expression, proinflammatory cytokine release and mitogen‐activated protein kinases in lipopolysaccharide‐activated BV2 microglia cells (Jung et al, ). However, the role of l ‐arginine‐nitric oxide pathway in the psychotropic effects of morin has not been fully investigated.…”