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  Indian J Med Microbiol
 

Figure 1: Proposed neuroprotective role of Withaferin A (WA) in the modulation of pathways implicated in neurological abnormalities and dysfunctions. Parkinson's disease (PD): WA is a known inhibitor of the Cdc37/Hsp90 complex. Inhibition of Cdc37/Hsp90 has resulted in a decrease of pathological protein LRRK2 in cellular models. WA exposure also increased the expression of p62 intracellularly, which could potentially be responsible for decreased levels of α-synuclein. WA also rescued low levels of dopamine (DA) and homovanillic acid (HVA) to improve motor deficits. Cerebral infarction (CI): In vitro WA treatment reduced expression of matrix metalloproteinases (MMPs), which mitigate VSMC migration and proliferation. In vivo the PI3K/Akt pathway was activated through induced CI, leading to a prevention of apoptosis. Reactive gliosis (RG): inhibition of both expression and polymerization of intermediate filaments (IFs) by WA led to a decrease in astrocyte reactivity and neuronal apoptosis. Amyotrophic lateral sclerosis (ALS): WA induced expression of Hsp25, which led to a decrease in mutant superoxide dismutase 1 (SOD1) and a decrease in neuronal apoptosis. Suppression of nuclear factor kappa B (NF-κB) by WA is linked to clearance of transactive response DNA-binding protein 43 (TDP-43). Human immunodeficiency virus-associated neurological dysfunctions (HIV-AND): WA treatment lowered amyloid beta (Aβ) aggregation in SH-APP cells. Reduced dendritic beading and cytoplasmic vacuoles were also shown in cells treated with WA. Uncertain until further study [INSIDE:1], leads to [INSIDE:2], prevents [INSIDE:3].

Figure 1: Proposed neuroprotective role of Withaferin A (WA) in the modulation of pathways implicated in neurological abnormalities and dysfunctions.
Parkinson's disease (PD): WA is a known inhibitor of the Cdc37/Hsp90 complex. Inhibition of Cdc37/Hsp90 has resulted in a decrease of pathological protein LRRK2 in cellular models. WA exposure also increased the expression of p62 intracellularly, which could potentially be responsible for decreased levels of α-synuclein. WA also rescued low levels of dopamine (DA) and homovanillic acid (HVA) to improve motor deficits. Cerebral infarction (CI): <i>In vitro</i> WA treatment reduced expression of matrix metalloproteinases (MMPs), which mitigate VSMC migration and proliferation. <i>In vivo</i> the PI3K/Akt pathway was activated through induced CI, leading to a prevention of apoptosis. Reactive gliosis (RG): inhibition of both expression and polymerization of intermediate filaments (IFs) by WA led to a decrease in astrocyte reactivity and neuronal apoptosis. Amyotrophic lateral sclerosis (ALS): WA induced expression of Hsp25, which led to a decrease in mutant superoxide dismutase 1 (SOD1) and a decrease in neuronal apoptosis. Suppression of nuclear factor kappa B (NF-κB) by WA is linked to clearance of transactive response DNA-binding protein 43 (TDP-43). Human immunodeficiency virus-associated neurological dysfunctions (HIV-AND): WA treatment lowered amyloid beta (Aβ) aggregation in SH-APP cells. Reduced dendritic beading and cytoplasmic vacuoles were also shown in cells treated with WA. Uncertain until further study [INSIDE:1], leads to [INSIDE:2], prevents [INSIDE:3].