In vitro anti-neuroinflammatory and neuritogenic stimulatory effects of a medicinal mushroom lignosus rhinocerotis (Cooke) ryvarden / Syntyche Seow Ling Sing
Neuroinflammation and neurite degeneration are contributing factors leading to the progression of neuronal loss and age-related neurodegenerative diseases e.g Alzheimer’s and Parkinson’s disease. Current drug therapy for neurodegenerative diseases is ineffective with many side effects and it is p...
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| Format: | Thesis |
| Published: |
2016
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| Online Access: | http://studentsrepo.um.edu.my/7015/4/ling_sing.pdf http://studentsrepo.um.edu.my/7015/ |
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| Summary: | Neuroinflammation and neurite degeneration are contributing factors leading to the
progression of neuronal loss and age-related neurodegenerative diseases e.g
Alzheimer’s and Parkinson’s disease. Current drug therapy for neurodegenerative
diseases is ineffective with many side effects and it is palliative and manages only the
symptoms of the diseases. In recent years, the attention of researchers has been inclined
towards the alternative and complementary approaches, such as dietary
supplementations and functional foods which have minimal side effects. Numerous
neuroactive substances from natural sources as preventive and therapeutic agents for
neurodegenerative diseases by promoting anti-neuroinflammatory and neuritogenic
stimulatory potential have received extensive attention. Among the natural sources
explored for anti-neuroinflammatory and neuritogenic stimulatory properties, medicinal
mushrooms have shown huge potential. In the present study, four medicinal mushrooms
were evaluated for cytotoxic, inhibition of nitric oxide (NO) production and
neuritogenic stimulatory activities in murine BV2 microglial and rat
pheochromocytoma (PC-12) cells. The preliminary results showed that the hot aqueous
extract of Lignosus rhinocerotis sclerotium significantly (p < 0.05) inhibited NO
production (75.57%) in lipopolysaccharides (LPS)-stimulated BV2 microglia and
stimulated 20.99 ± 1.01% of neurite bearing cells in PC-12 cells that comparable to the
positive control, 50 ng/ml of nerve growth factor (NGF). The hot aqueous extract of L.
rhinocerotis sclerotium was not cytotoxic to BV2 and PC-12 cells after 48 hours of
exposure. The hot aqueous extract of L. rhinocerotis sclerotium was further fractionated
into three solvent fractions: ethyl acetate, n-butanol and aqueous fractions. The antineuroinflammatory
and neuritogenic stimulatory effects of the solvent fractions and the
underlying mechanisms were investigated. The results demonstrated that ethyl acetate
and n-butanol fractions (125 and 250 μg/ml) inhibited the production of proinflammatory
mediators and cytokines, including NO, prostaglandin E2 (PGE2), tumor
necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), and the expressions of inducible
nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), TNF-α, IL-1β and IL-6 in
LPS-stimulated BV2 microglia. The anti-neuroinflammatory effects of ethyl acetate and
n-butanol fractions are mediated through the suppression of the toll-like receptor 4
(TLR4), mitogen-activated protein kinases (MAPKs) (extracellular signal-regulated
kinases1/2 (ERK1/2), stress-activated protein kinases/jun amino-terminal kinases
(SAPK/JNK) and p-38 MAPK), protein kinase B (AKT) and nuclear factor-kappaB
(NFκB) signaling pathways with the inhibition of the transcription factors, cyclic
adenosine monophosphate (cAMP) response element-binding protein (CREB), activator
protein 1 (AP-1) and NFκB. The ethyl acetate and n-butanol fractions (10 μg/ml)
significantly (p < 0.05) stimulated a higher percentage of neurite bearing cells compared
to NGF (50 ng/ml) without stimulating the production of NGF in PC-12 cells. The ethyl
acetate and n-butanol fractions mimicked the neuritogenic activity of NGF by targeting
the tropomyosin receptor kinase A (TrkA) receptor and activated the mitogen-activated
protein kinase kinase (MEK)/ERK1/2 and phosphoinositide 3-kinase
(PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathways with the
phosphorylation of CREB, and leading to the increased expressions of neuritogenesis
biomarker, the growth associated protein 43 (GAP43), tubulin alpha 4A (TUBA4A) and
tubulin beta 1 (TUBB1) in PC-12 cells. In conclusion, the present findings demonstrated
that L. rhinocerotis sclerotium mitigated neuroinflammation and stimulated
neuritogenesis in BV2 and PC-12 cells, respectively. |
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