Characterizing the protracted neurobiological and neuroanatomical effects of paraquat in a murine model of Parkinson's disease

Dwyer, Zach; Rudyk, Chris; Farmer, Kyle; Beauchamp, Sheryl; Shail, Pragya; Derksen, Alexa; Fortin, T.; Ventura, Katelyn; Torres, Carlos; Ayoub, Kiara; Hayley, Shawn

doi:10.1016/j.neurobiolaging.2020.11.013

Cited by 21 publications

(10 citation statements)

References 63 publications

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“…In agreement with our results, previous investigations showed that PQ increased airway resistance and tracheal responsiveness to methacholine via modifying ROS production in the lung in mice compared to the control group 32,33 . The results also displayed that inhaled PQ decreased body weight significantly compared to the control group which is also confirmed by a previous study 34 …”

Section: Discussionsupporting

confidence: 93%

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A dose‐related positive effect of inhaled simvastatin‐loaded PLGA nanoparticles on paraquat‐induced pulmonary fibrosis in rats

Shahabadi

Moshiri

Roohbakhsh

et al. 2022

Basic Clin Pharma Tox

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Objective Pulmonary fibrosis is an important complication of subacute paraquat (PQ) poisoning. Here, we reported a novel nanotherapeutic platform for PQ‐induced pulmonary fibrosis in animal inhalation models using simvastatin (SV)‐loaded into poly(lactic‐co‐glycolic acid) (PLGA) nanoparticles (NPs). Methods and Materials Eight inhalations of normal saline, PQ (24 mg/kg), PQ plus SV (20 mg/kg), PQ plus SV‐loaded PLGA NPs at doses of 5, 10 or 20 mg/kg or PQ plus PLGA NPs were given to rats. After the end of the treatment period, inflammatory factors and creatine phosphokinase as well as lung pathological changes and tracheal responsiveness were evaluated. Results Inhalation of SV‐loaded PLGA NPs could significantly prevent the progression of PQ‐induced pulmonary fibrosis especially at a dose of 10 mg through decreasing the serum level of inflammatory factors as well as contractile responses (p < 0.001) compared to PQ group. Pathological findings also confirmed the results. However, inhalation of non‐formulated SV could not prevent tissue damage and fibrosis in comparision with SV‐loaded PLGA NPs. Conclusion Taken together, the present work provides us an idea about the pulmonary delivery of PLGA‐SV NPs using nebulizer for the treatment of PQ poisoning. However, the efficacy of this formulation in human beings and clinical use needs to be more investigated.

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Section: Discussionsupporting

confidence: 93%

“…32,33 The results also displayed that inhaled PQ decreased body weight significantly compared to the control group which is also confirmed by a previous study. 34 Simvastatin has been suggested as a potential new treatment for inflammatory respiratory diseases due to muco-inhibitory property, immunomodulatory and antiinflammatory effects.…”

Section: Discussionmentioning

confidence: 99%

A dose‐related positive effect of inhaled simvastatin‐loaded PLGA nanoparticles on paraquat‐induced pulmonary fibrosis in rats

Shahabadi

Moshiri

Roohbakhsh

et al. 2022

Basic Clin Pharma Tox

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“…S2), consistent with its activation. PQ activates NF-κB in tissues like brain 31 and lung 32 via a direct interaction with TLR4/9 receptors. Recent data indicates that fragmented, expulsed mtDNA arising from oxidative damage promotes pro-inflammatory events such as NF-κB translocation 33 .…”

Section: Resultsmentioning

confidence: 99%

Small molecule-mediated allosteric activation of the base excision repair enzyme 8-oxoguanine DNA glycosylase and its impact on mitochondrial function

Tian

Katchur

Jiang

et al. 2022

Sci Rep

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Abstract8-Oxoguanine DNA glycosylase (OGG1) initiates base excision repair of the oxidative DNA damage product 8-oxoguanine. OGG1 is bifunctional; catalyzing glycosyl bond cleavage, followed by phosphodiester backbone incision via a β-elimination apurinic lyase reaction. The product from the glycosylase reaction, 8-oxoguanine, and its analogues, 8-bromoguanine and 8-aminoguanine, trigger the rate-limiting AP lyase reaction. The precise activation mechanism remains unclear. The product-assisted catalysis hypothesis suggests that 8-oxoguanine and analogues bind at the product recognition (PR) pocket to enhance strand cleavage as catalytic bases. Alternatively, they may allosterically activate OGG1 by binding outside of the PR pocket to induce an active-site conformational change to accelerate apurinic lyase. Herein, steady-state kinetic analyses demonstrated random binding of substrate and activator. 9-Deazaguanine, which can’t function as a substrate-competent base, activated OGG1, albeit with a lower Emax value than 8-bromoguanine and 8-aminoguanine. Random compound screening identified small molecules with Emax values similar to 8-bromoguanine. Paraquat-induced mitochondrial dysfunction was attenuated by several small molecule OGG1 activators; benefits included enhanced mitochondrial membrane and DNA integrity, less cytochrome c translocation, ATP preservation, and mitochondrial membrane dynamics. Our results support an allosteric mechanism of OGG1 and not product-assisted catalysis. OGG1 small molecule activators may improve mitochondrial function in oxidative stress-related diseases.

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“…S2e), consistent with its activation. PQ activates NF-kB in tissues like brain [31] and lung [32] via a direct interaction with TLR4/9 receptors. Recent data indicates that fragmented, expulsed mtDNA arising from oxidative damage promotes pro-in ammatory events such as NF-κB translocation [33].…”

Section: Resultsmentioning

confidence: 99%

Small Molecule-Mediated Allosteric Activation of the Base Excision Repair Enzyme 8-Oxoguanine DNA Glycosylase: Impact on Mitochondrial Function

Tian¹,

Katchur²,

Jiang³

et al. 2022

Preprint

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8-Oxoguanine DNA glycosylase (OGG1) initiates base excision repair of the oxidative DNA damage product 8-oxoguanine. OGG1 is bifunctional; catalyzing glycosyl bond cleavage, followed by phosphodiester backbone incision via a β-elimination apurinic lyase reaction. The product from the glycosylase reaction, 8-oxoguanine, and its analogues, 8-bromoguanine and 8-aminoguanine, trigger the rate-limiting AP lyase reaction. The precise activation mechanism remains unclear. The product-assisted catalysis hypothesis suggests that 8-oxoguanine and analogues bind at the product recognition (PR) pocket to enhance strand cleavage as catalytic bases. Alternatively, they may allosterically activate OGG1 by binding outside of the PR pocket to induce an active-site conformational change to accelerate apurinic lyase. Herein, steady-state kinetic analyses demonstrated random binding of substrate and activator. 9-Deazaguanine, which can’t function as a substrate-competent base, activated OGG1, albeit with a lower Emax value than 8-bromoguanine and 8-aminoguanine. Random compound screening identified small molecules with Emax values similar to 8-bromoGua. Paraquat-induced mitochondrial dysfunction was attenuated by several small molecule OGG1 activators; benefits included enhanced mitochondrial membrane and DNA integrity, less cytochrome c translocation, ATP preservation, and mitochondrial membrane dynamics. Our results support an allosteric mechanism of OGG1 and not product-assisted catalysis. OGG1 small molecule activators may improve mitochondrial function in oxidative stress-related diseases.

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Characterizing the protracted neurobiological and neuroanatomical effects of paraquat in a murine model of Parkinson's disease

Cited by 21 publications

References 63 publications

A dose‐related positive effect of inhaled simvastatin‐loaded PLGA nanoparticles on paraquat‐induced pulmonary fibrosis in rats

A dose‐related positive effect of inhaled simvastatin‐loaded PLGA nanoparticles on paraquat‐induced pulmonary fibrosis in rats

Small molecule-mediated allosteric activation of the base excision repair enzyme 8-oxoguanine DNA glycosylase and its impact on mitochondrial function

Small Molecule-Mediated Allosteric Activation of the Base Excision Repair Enzyme 8-Oxoguanine DNA Glycosylase: Impact on Mitochondrial Function

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