In a recent review published within the Journal of Ginseng Research, researchers discussed the therapeutic potential of Panax ginseng for COVID-19 (coronavirus disease 2019)-induced neurological diseases.
Study: Panax ginseng as a possible therapeutic for neurological disorders related to COVID-19; Toward targeting inflammasome. Image Credit: QinJin/Shutterstock
Background
SARS-CoV-2 (severe acute respiratory syndrome-coronavirus-2) infections may cause a myriad of clinical manifestations involving multiple organ systems, including the nervous system (NS). NLRP3 (nucleotide-binding oligomerization domain-like receptor pyrin domain-containing-3) inflammasomes are multiprotein complexed that detect PAMPs (pathogen-associated molecular patterns) and DAMPs (damage-associated MPs) generated in neurological diseases.
P. ginseng is a traditional medicinal herb used widely for enhancing immunity and treating several pathological NS disorders conditions. Recent studies have reported that the lively components of P. ginseng (corresponding to saponins and ginsenosides) could regulate the activation of NLRP3 inflammasomes in NS.
In regards to the review
In the current study, researchers discussed existing literature regarding the SARS-CoV-2-induced neurodegeneration pathogenesis involving the activation of NLRP3 inflammasomes and the potential effectiveness of P. ginseng for NLRP3-targeted treatment of neurological diseases.
Neuropathogenesis of SARS-CoV-2 infections
Neurological diseases corresponding to stroke and Alzheimer’s disease have increasingly been identified as consequences of SARS-CoV-2 infections. Neurological manifestations may be divided into musculoskeletal system manifestations, central NS (CNS) manifestations (corresponding to headache, vertigo, stroke, ataxia, anosmia, and seizures), and peripheral NS (PNS) manifestations (corresponding to neuropathic pain and smell/vision/taste impairments).
SARS-CoV-2 invades the NS via two mechanisms: (i) SARS-CoV-2 binds to the angiotensin-converting enzyme 2 (ACE2) receptors or modifies the tight junction proteins between the adjoining BBB (blood-brain barrier) endothelial cells or (ii) SARS-CoV-2 is phagocytosed by immunological cells and subsequently invades the CNS by the hematogenous or non-hematogenous spread.
In response to SARS-CoV-2-associated neurological injury and associated PAMP and DAMP formation, NLRP3 inflammasome is assembled and activated, stimulating the production of caspase-1-mediated interleukin (IL)-1β, IL-18, and other cytokines corresponding to IL-6,12, and tumor necrosis factor-alpha (TNF-α) by immunological cells. Subsequently, NLP3 may very well be targeted to develop anti-SARS-CoV-2 therapeutic agents.
NLRP3 assembly involves two phases, priming, and activation. The priming phase is triggered by the signaling of pattern recognition receptors, corresponding to toll-like receptors (TLRs) and TNF receptors (TNFRs). Receptor activation causes transcriptional activation of pro-IL-18, pro-IL-1β and NLRP3 via NF-κB (nuclear factor kappa B)-mediated transcriptional regulation.
The second step involves NLRP3 and ASC assembly into the inflammasome multiprotein complex initiated by ionic flux-stimulated NLRP3 stimulation (K+ and CL- efflux, Ca+ and Na+ influx), mitochondrial dysfunction, reactive oxygen species (ROS), lysosomal injury, adenosine triphosphate (ATP), and caspase-1 activation.
NLRP3 inflammasomes are initially expressed in inflammatory and immunological cells, including microglia, neutrophils, macrophages, and mast cells. Microglia are key cells involved in neuroinflammation, and balancing the M1(inflammatory)/M2 (anti-inflammatory) microglia polarization is a possible therapeutic strategy for COVID-19-associated neurodegeneration.
Currently used approaches
Antiviral drugs corresponding to paxlovid, remdesivir, and molnupiravir have been effective against SARS-CoV-2; nevertheless, they’re related to hostile effects. Essentially the most frequent unwanted side effects of remdesivir use include pulmonary failure, and organ dysfunction, with lowered albumin and potassium levels and erythrocyte and platelet counts, contributing to yellowish skin discoloration and blood clot formation.
P. ginseng is a medicinal herb with anti-inflammatory/oxidant/aging/neurodegenerative, restorative activities, and cognitive and memory-enhancing activities with fewer unwanted side effects than the currently used antiviral drugs. The herb has demonstrated efficacy against influenza and pneumonia in several in vivo studies. Korean red ginseng (KRG) extract (KRGE) inhibits IL-1β and caspase-1 production and ASC (apoptosis-associated speck-like protein with CARD domain) pyroptosome formation.
The herb’s saponins inhibit NLRP3 and pro-IL-1β transcription and translation on the initial (priming) step. KRGE saponins have shown anti-inflammatory effects by ameliorating the messenger ribonucleic acid (mRNA) expression of genes encoding NLRP3 inflammasome components corresponding to pro-IL-1β and pro-caspase-1 in mice. Ginsenoside Rd, a component of P. ginseng, reduces OGD/R (oxygen-glucose deprivation/reoxygenation)-induced BV-2 microglial cell injury by suppressing NLRP3 inflammasome activation and inhibiting dynamin-associated protein 1-mediated mitochondrial fission.
Ginsenoside Rg1 inhibits IL-1β-induced neuroinflammation by regulating NF-κB pathways, inhibits microglia pyroptosis, and inhibits NLRP3 inflammasome production by regulating the signal transducer and activator of transcription 2 (STAT2) pathway. Ginsenoside Rh1 and Rg3 reduce IL-1β production induced by LPS and downregulate NLRP3 inflammasomes. Compound K (secondary ginsenoside), and Notoginsenoside R1 (P. notoginseng component) can ameliorate oxidative stress.
Non-saponin components downregulate TLR4 mRNA and protein expression and attenuate cytokine production. GEF (gintonin-enriched fraction) suppresses NLRP3 expression through lysophosphatidic acid receptors (LPARs). Further, CPA (combination of P. ginseng and Angelica sinensis) and ginsenoside Rd- Z-ligustilide mixtures reduce NLRP3 inflammasome activation.
Overall, the review findings highlighted the potential therapeutic use of P. ginseng for neurological diseases related to SARS-CoV-2 infections via NLRP3 inflammasome regulation.