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Abstract
Parkinson’s disease, the second common neurodegenerative disease is clinically characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) with upregulation of neuroinflammatory markers and oxidative stress. Autophagy lysosome pathway (ALP) plays a major role in degradation of damaged organelles and proteins for energy balance and intracellular homeostasis. However, dysfunction of ALP results in impairment of α-synuclein clearance which hastens dopaminergic neurons loss. In this study, we wanted to understand the neuroprotective efficacy of Val in rotenone induced PD rat model. Animals received intraperitoneal injections (2.5 mg/kg) of rotenone daily followed by Val (40 mg/kg, i.p) for four weeks. Valeric acid, a straight chain alkyl carboxylic acid found naturally in Valeriana officianilis have been used in the treatment of neurological disorders. However, their neuroprotective efficacy has not yet been studied. In our study, we found that Val prevented rotenone induced upregulation of pro-inflammatory cytokine oxidative stress, and α-synuclein expression with subsequent increase in vital antioxidant enzymes. Moreover, Val mitigated rotenone induced hyperactivation of microglia and astrocytes. These protective mechanisms prevented rotenone induced dopaminergic neuron loss in SNpc and neuronal fibers in the striatum. Additionally, Val treatment prevented rotenone blocked mTOR-mediated p70S6K pathway as well as apoptosis. Moreover, Val prevented rotenone mediated autophagic vacuole accumulation and increased lysosomal degradation. Hence, Val could be further developed as a potential therapeutic candidate for treatment of PD.
Highlights
Parkinson’s disease (PD), the second most common neurodegenerative disease is characterized by motor impairments such as bradykinesia, rigidity, tremor and postural abnormalities but cognitive, emotional and olfactory abnormalities are seen in PD patients [1,2]
We found that rotenone mediated increase in oxidative stress amplifies activation of microglia and astrocyte [58]
Duke et al, 2007 reported an increase in expression of genes encoding pro-inflammatory cytokines in substantia nigra of PD patients [63]. In line with these reports, we found that rotenone administration caused hyper-activation of microglia and astrocyte (Figure 3) which inturn enhanced the expression of IL-6, IL-1β, TNF-α, NO, MMP-9, COX-2 and inducible nitric oxide synthase (iNOS) (Figure 2)
Summary
Parkinson’s disease (PD), the second most common neurodegenerative disease is characterized by motor impairments such as bradykinesia, rigidity, tremor and postural abnormalities but cognitive, emotional and olfactory abnormalities are seen in PD patients [1,2]. PET imaging studies have proved widespread microglial response in PD patients with subsequent augmentation of oxidative and nitrosative stress [14,15], fueling inflammation mediated neurodegeneration, Astrocytes which represents 50% of glial population are being studied for its significant role in initiation of PD. It has been reported that astrocytic alpha-synuclein deposits trigger recruitment of activated microglia that executes neurons resulting in PD [16,17]. Various pathways initiates toxic events leading to neurodegeneration, the most common cause of PD pathogenesis is due to abundant deposition of misfolded proteins (α-synuclein) and impairment of protein degradation pathways leading to neuronal death. One such important protein degradation mechanism is called autophagy. Restoration of mTOR, 4E-BP1 or p70S6K significantly protected neurons against PD mimetics [31,32]
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