Recently, we demonstrated that dimeric apocynin prevented loss of motor function in the leucine-rich repeat kinase 2 (LRRK2R1441G) transgenic (tg) mouse (treated with 200 mg/kg, three times per week) [B.P. Dranka et al., Neurosci. Lett. 549 (2013) 57-62]. Here we extend those studies by treating LRRK2R1441G mice with an orally-available, mitochondrially-targeted apocynin derivative. We hypothesized that the increased mitochondrial permeability of Mito-apocynin, due to the triphenylphosphonium moiety, would allow improvement of Parkinson’s disease (PD) symptoms at lower doses than those required for diapocynin. Tests of motor coordination (pole test, Rotor-Rod) revealed a significant deficit in coordinated motor function in LRRK2R1441G mice by 15 months of age. Decreased performance on the pole test and Rotor-Rod in the LRRK2R1441G mice was prevented with Mito-apocynin treatment (3 mg/kg, three times per week). Decreased olfactory function is an early indication of PD in human patients. LRRK2R1441G tg mice displayed deficits in sense of smell in both the hidden treat test, and a radial arm maze test. Interestingly, treatment with Mito-apocynin prevented this hyposmia, and animals retained normal ability to identify either a scented treat or a food pellet as well as wild type littermates. Together, these data demonstrate that the mitochondria-targeted apocynin analog is effective in preventing early PD-like symptoms in the LRRK2R1441G mouse model.

The most prominent mechanism proposed for death of dopaminergic neurons in Parkinson’s disease (PD) is elevated generation of reactive oxygen/nitrogen species (ROS/RNS). Recent studies suggest that ROS produced during PD pathogenesis may contribute to cytotoxicity in cell culture models of PD. We hypothesized that inhibition of ROS production would prevent PD symptoms in the LRRK2R1441G transgenic (tg) mouse model of PD. These mice overexpress a mutant form of leucine-rich repeat kinase 2 (LRRK2) and are reported to develop PD-like symptoms at approximately 10 months of age. Despite similar expression of the transgene, our colony did not recapitulate the same type of motor dysfunction originally reported. However, tests of motor coordination (pole test, Rotor-Rod) revealed a significant defect in LRRK2R1441G mice by 16 months of age. LRRK2R1441G tg mice, or wild type littermates, were given diapocynin (200 mg/kg, a proposed NADPH oxidase inhibitor) three times per week by oral gavage starting at 12 weeks of age. Decreased performance on the pole test and Rotor-Rod in the LRRK2R1441G mice was prevented with diapocynin treatment. No loss in open field movement or rearing was found. As expected, tyrosine hydroxylase staining was similar in both the substantia nigra and striatum in all treatment groups. Together these data demonstrate that diapocynin is a viable agent for protection of neurobehavioral function.

Background and objectives Because of its beneficial off‐target effects against non‐mycobacterial infectious diseases, bacillus Calmette–Guérin (BCG) vaccination might be an accessible early intervention to boost protection against novel pathogens. Multiple epidemiological studies and randomised controlled trials (RCTs) are investigating the protective effect of BCG against coronavirus disease 2019 (COVID‐19). Using samples from participants in a placebo‐controlled RCT aiming to determine whether BCG vaccination reduces the incidence and severity of COVID‐19, we investigated the immunomodulatory effects of BCG on in vitro immune responses to SARS‐CoV‐2. Methods This study used peripheral blood taken from participants in the multicentre RCT and BCG vaccination to reduce the impact of COVID‐19 on healthcare workers (BRACE trial). The whole blood taken from BRACE trial participants was stimulated with γ‐irradiated SARS‐CoV‐2‐infected or mock‐infected Vero cell supernatant. Cytokine responses were measured by multiplex cytokine analysis, and single‐cell immunophenotyping was made by flow cytometry. Results BCG vaccination, but not placebo vaccination, reduced SARS‐CoV‐2‐induced secretion of cytokines known to be associated with severe COVID‐19, including IL‐6, TNF‐α and IL‐10. In addition, BCG vaccination promoted an effector memory phenotype in both CD4+ and CD8+ T cells, and an activation of eosinophils in response to SARS‐CoV‐2. Conclusions The immunomodulatory signature of BCG’s off‐target effects on SARS‐CoV‐2 is consistent with a protective immune response against severe COVID‐19.

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