Systemic and targeted activation of Nrf2 reverses doxorubicin-induced cognitive impairments and sensorimotor deficits in mice.

While cancer survivorship has increased due to advances in treatments, chemotherapy often carries long-lived neurotoxic side effects which reduce quality of life. Commonly affected domains include memory, executive function, attention, processing speed and sensorimotor function, colloquially known as chemotherapy-induced cognitive impairment (CICI) or "chemobrain". Oxidative stress and neuroimmune signaling in the brain have been mechanistically linked to the deleterious effects of chemotherapy on cognition and sensorimotor function. With this in mind, we tested if activation of the master regulator of antioxidant response nuclear factor E2-related factor 2 (Nrf2) alleviates cognitive and sensorimotor impairments induced by doxorubicin. The FDA-approved systemic Nrf2 activator, diroximel fumarate (DRF) was used, along with our recently developed prodrug 1c which has the advantage of specifically releasing monomethyl fumarate at sites of oxidative stress. DRF and 1c both reversed doxorubicin-induced deficits in executive function, spatial and working memory, as well as decrements in fine motor coordination and grip strength, across both male and female mice. Both treatments reversed doxorubicin-induced loss of synaptic proteins and microglia phenotypic transition in the hippocampus. Doxorubicin-induced myelin damage in the corpus callosum was reversed by both Nrf2 activators. These results demonstrate the therapeutic potential of Nrf2 activators to reverse doxorubicin-induced cognitive impairments, motor incoordination, and associated structural and phenotypic changes in the brain. The localized release of monomethyl fumarate by 1c has the potential to diminish unwanted effects of fumarates while retaining efficacy.

Resveratrol Regulates Nrf2-Mediated Expression of Antioxidant and Xenobiotic Metabolizing Enzymes in Pesticides-Induced Parkinsonism.

BACKGROUND: Combined maneb (MB) and paraquat (PQ), two widely used pesticides, increases oxidative stress leading to Parkinsonism. Xenobiotic metabolizing enzymes, cytochrome P450 (CYP) 2D6 and its mouse ortholog Cyp2d22 protect against Parkinsonism. Resveratrol, an antioxidant, restores antioxidant defense system through the activation of nuclear factor erythroid 2- related factor 2 (Nrf2). However, a crosstalk between Cyp2d22/CYP2D6-mediated protection and resveratrol-induced Nrf2 activation leading to neuroprotection is not yet elucidated. OBJECTIVE: The study aimed to decipher the effect of resveratrol on Nrf2 activation and expression of its downstream mediators, nicotinamide adenine dinucleotide phosphate quinone oxidoreductase 1 (NQO1) and thioredoxin 1 (Trx1) along with Cyp2d22/CYP2D6 activity in combined MB and PQ mouse model of Parkinsonism and differentiated neuroblastoma cells. RESULTS: MB and PQ reduced the dopamine content (mouse) and Cyp2d22/CYP2D6 activity (mouse/neuroblastoma cells) and increased the nuclear translocation of Nrf2 and expression of NQO1 and Trx1 (both). Resveratrol ameliorated pesticides-induced changes in dopamine content and Cyp2d22/CYP2D6 activity. It was found to promote nuclear translocation of Nrf2 and expression of NQO1 and Trx1 proteins. Since Cyp2d22/CYP2D6 inhibitor (ketoconazole/quinidine) per se reduced Cyp2d22/CYP2D6 activity and dopamine content, it was found to substantially increase the pesticides-induced reduction in Cyp2d22/CYP2D6 activity and dopamine content. Inhibitors normalized the pesticides induced changes in Nrf2 translocation and NQO1 and Trx1 levels in pesticides treated groups. CONCLUSION: The results suggest that resveratrol promotes the catalytic activity of xenobiotic metabolizing enzyme, Cyp2d22/CYP2D6, which partially contributes to Nrf2 activation in pesticides- induced Parkinsonism.

Silymarin Protects Against Impaired Autophagy Associated with 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-Induced Parkinsonism.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exacerbates mitochondrial impairment and α-synuclein expression leading to Parkinsonism. Impaired mitochondria and over-expressed α-synuclein are degraded and eliminated via macroautophagy and chaperone-mediated autophagy. Owing to multiple properties, silymarin protects from oxidative stress-mediated cellular injury. However, its effect on MPTP-induced changes in autophagy is not yet known. The study aimed to decipher the effect of silymarin on MPTP-induced changes in autophagy. Male mice (20-25 g) were treated with silymarin (intraperitoneally, daily, 40 mg/kg) for 2 weeks. On day 7, a few animals were also administered with MPTP (intraperitoneally, 20 mg/kg, 4 injections at 2-h interval) along with vehicles. Striatal dopamine content was determined. Western blot analysis was done to assess α-synuclein, beclin-1, sequestosome, phosphorylated 5' adenosine monophosphate-activated protein kinase (p-AMPK), lysosome-associated membrane protein-2 (LAMP-2), heat shock cognate-70 (Hsc-70), LAMP-2A, phosphorylated unc-51-like autophagy activating kinase (p-Ulk1), and phosphorylated mechanistic target of rapamycin (p-mTOR) levels in the nigrostriatal tissue. Silymarin rescued from MPTP-induced increase in beclin-1, sequestosome, p-AMPK, and p-Ulk1 and decrease in LAMP-2, p-mTOR, and LAMP-2A levels. Silymarin defended against MPTP-induced increase in α-synuclein and reduction in dopamine content. The results demonstrate that silymarin protects against MPTP-induced changes in autophagy leading to Parkinsonism.