1α,25-Dihydroxyvitamin D3 (VD3) Shows a Neuroprotective Action Against Rotenone Toxicity on PC12 Cells: An In Vitro Model of Parkinson’s Disease

Siqueira, Erlânia Alves de; Magalhães, Emanuel Paula; Assis, Albert Layo Costa de; Sampaio, Tiago Lima; Lima, Dânya Bandeira; Marinho, Márcia Machado; Martins, Alice Maria Costa; Andrade, Geanne Matos de; Viana, Glauce Socorro de Barros

doi:10.1007/s11064-022-03735-5

Cited by 6 publications

(3 citation statements)

References 74 publications

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“…It has been reported that PD had less VD3 than the control population in recent years. The evidence supported that VD3 presented anti-inflammatory and improved mitochondrial function in PD models (37,38). However, the role of VD3 in cuproptosis has not been clarified.…”

Section: Discussionmentioning

confidence: 83%

Significance of Cuproptosis-related genes in immunological characterization, diagnosis and clusters classification in Parkinson's disease

Zhe Zhong,

Huiqing Wang,

Min Ye

et al. 2023

Cell Mol Biol (Noisy-le-grand)

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Section: Discussionmentioning

confidence: 83%

Significance of Cuproptosis-related genes in immunological characterization, diagnosis and clusters classification in Parkinson's disease

Zhe Zhong,

Huiqing Wang,

Min Ye

et al. 2023

Cell Mol Biol (Noisy-le-grand)

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“…Upon nuclear translocation, Nrf2 stimulates the transcription of multiple antioxidant and anti-inflammatory genes after binding to antioxidant response elements (ARE) located in the promoter region of those genes (Magesh et al 2012 ). Thus, Nrf2 activators could be effective in breaking down α-syn aggregates and hampering NF-κB-associated neuroinflammation elucidated in PD via maintaining cellular redox homeostasis (Chakkittukandiyil et al 2022 ; de Siqueira et al 2023 ). Our results clarified that roflumilast ameliorates rotenone-induced neurotoxicity by upsurging striatal Nrf2 expression along with downregulating Keap 1 expression, which is in line with a previous study showing the neuroprotective effect of roflumilast against ischemic stroke-induced neuronal damage via activating Nrf2 (Xu et al 2021 ).…”

Section: Discussionmentioning

confidence: 99%

PI3K/AKT signaling activation by roflumilast ameliorates rotenone-induced Parkinson’s disease in rats

et al. 2023

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Parkinson’s disease (PD) is the second most common progressive age-related neurodegenerative disorder. Paramount evidence shed light on the role of PI3K/AKT signaling activation in the treatment of neurodegenerative disorders. PI3K/AKT signaling can be activated via cAMP-dependent pathways achieved by phosphodiesterase 4 (PDE4) inhibition. Roflumilast is a well-known PDE4 inhibitor that is currently used in the treatment of chronic obstructive pulmonary disease. Furthermore, roflumilast has been proposed as a favorable candidate for the treatment of neurological disorders. The current study aimed to unravel the neuroprotective role of roflumilast in the rotenone model of PD in rats. Ninety male rats were allocated into six groups as follows: control, rotenone (1.5 mg/kg/48 h, s.c.), L-dopa (22.5 mg/kg, p.o), and roflumilast (0.2, 0.4 or 0.8 mg/kg, p.o). All treatments were administrated for 21 days 1 h after rotenone injection. Rats treated with roflumilast showed an improvement in motor activity and coordination as well as preservation of dopaminergic neurons in the striatum. Moreover, roflumilast increased cAMP level and activated the PI3K/AKT axis via stimulation of CREB/BDNF/TrkB and SIRT1/PTP1B/IGF1 signaling cascades. Roflumilast also caused an upsurge in mTOR and Nrf2, halted GSK-3β and NF-ĸB, and suppressed FoxO1 and caspase-3. Our study revealed that roflumilast exerted neuroprotective effects in rotenone-induced neurotoxicity in rats. These neuroprotective effects were mediated via the crosstalk between CREB/BDNF/TrkB and SIRT1/PTP1B/IGF1 signaling pathways which activates PI3K/AKT trajectory. Therefore, PDE4 inhibition is likely to offer a reliable persuasive avenue in curing PD via PI3K/AKT signaling activation. Graphical Abstract

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“…PC12 cells are derived from rat chromaffin cells (pheochromocytes). As chromaffin cells constitute the largest and most homogenous collection of catecholamine synthesizing cells in mammalian tissues, primary chromaffin cells and PC12 cells are preferred model systems for mechanistic studies of DA synthesis-related cellular processes, including regulation of TH activity (de Siqueira et al, 2023; Lisek et al, 2022). Our studies are comparable to previous investigations on the effects on elevating L-Phe and L-Tyr levels in PC12 cells (DePietro & Fernstrom, 1998).…”

Section: Discussionmentioning

confidence: 99%

The effects of phenylalanine and tyrosine levels on dopamine production in rat PC12 cells. Implications for treatment of phenylketonuria and tyrosinemia type 1

Szigetvari,

Patil,

Birkeland

et al. 2023

Preprint

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Phenylketonuria (PKU) is an autosomal recessive metabolic disorder caused by mutations in the phenylalanine hydroxylase (PAH) gene, resulting in phenylalanine accumulation and impaired tyrosine production. In Tyrosinemia type 1 (TYRSN1) mutations affect fumarylacetoacetate hydrolase, leading to accumulation of toxic intermediates of tyrosine catabolism. Treatment of TYRSN1 with nitisinone results in extreme tissue levels of tyrosine. Although PKU and TYRSN1 have opposite effects on tyrosine levels, both conditions have been associated with neuro-psychiatric symptoms indicative of impaired dopamine (DA) synthesis. However, concrete in vivo data on the possible molecular basis for disrupted DA production under disease mimicking conditions have been lacking. In pursuit to uncover associated molecular mechanisms, we exposed an established, DA producing cell line (PC12) to different concentrations of phenylalanine and tyrosine in culture media. We measured the effects on viability, proteomic composition, tyrosine, DA and tyrosine hydroxylase (TH) levels and TH phosphorylation. TH catalyzes the rate-limiting step in DA synthesis. High extracellular levels of phenylalanine rapidly depleted cells of intracellular tyrosine and DA. Compared to physiological levels (75 μM), either low (35 μM) or high concentrations of tyrosine (275 or 835 μM) decreased cellular DA, TH protein, and its phosphorylation levels. Using deep proteomic analysis, we identified multiple proteins, biological processes and pathways that were altered, including enzymes and transporters involved in amino acid metabolism. Specifically, levels of the broad specificity transporter of neutral amino acids LAT1 and the branched-chain amino-acid-transporter BCAT2 were both similarly increased. Using this information and published data, we developed a mathematical model to predict how extracellular levels of aromatic amino acids can affect the cellular synthesis of DA via different mechanisms. Together, these data provide new information about the normal regulation of neurotransmitter synthesis and how this may be altered on the molecular level in neurometabolic disorders, such as PKU and TYRSN1.

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1α,25-Dihydroxyvitamin D3 (VD3) Shows a Neuroprotective Action Against Rotenone Toxicity on PC12 Cells: An In Vitro Model of Parkinson’s Disease

Cited by 6 publications

References 74 publications

Significance of Cuproptosis-related genes in immunological characterization, diagnosis and clusters classification in Parkinson's disease

Significance of Cuproptosis-related genes in immunological characterization, diagnosis and clusters classification in Parkinson's disease

PI3K/AKT signaling activation by roflumilast ameliorates rotenone-induced Parkinson’s disease in rats

The effects of phenylalanine and tyrosine levels on dopamine production in rat PC12 cells. Implications for treatment of phenylketonuria and tyrosinemia type 1

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