Abstract
The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is commonly used to model Parkinson’s disease (PD) as it specifically damages the nigrostriatal dopaminergic pathway. Recent studies in mice have, however, provided evidence that MPTP also compromises the integrity of the brain’s vasculature. Photobiomodulation (PBM), the irradiation of tissue with low-intensity red light, mitigates MPTP-induced loss of dopaminergic neurons in the midbrain, but whether PBM also mitigates MPTP-induced damage to the cerebrovasculature has not been investigated. This study aimed to characterize the time course of cerebrovascular disruption following MPTP exposure and to determine whether PBM can mitigate this disruption. Young adult male C57BL/6 mice were injected with 80 mg/kg MPTP or isotonic saline and perfused with fluorescein isothiocyanate FITC-labelled albumin at various time points post-injection. By 7 days post-injection, there was substantial and significant leakage of FITC-labelled albumin into both the substantia nigra pars compacta (SNc; p < 0.0001) and the caudate-putamen complex (CPu; p ≤ 0.0003); this leakage partly subsided by 14 days post-injection. Mice that were injected with MPTP and treated with daily transcranial PBM (670 nm, 50 mW/cm2, 3 min/day), commencing 24 h after MPTP injection, showed significantly less leakage of FITC-labelled albumin in both the SNc (p < 0.0001) and CPu (p = 0.0003) than sham-treated MPTP mice, with levels of leakage that were not significantly different from saline-injected controls. In summary, this study confirms that MPTP damages the brain’s vasculature, delineates the time course of leakage induced by MPTP out to 14 days post-injection, and provides the first direct evidence that PBM can mitigate this leakage. These findings provide new understanding of the use of the MPTP mouse model as an experimental tool and highlight the potential of PBM as a therapeutic tool for reducing vascular dysfunction in neurological conditions.
Highlights
MethodsAll protocols were approved by the University of Sydney Animal Ethics Committee
Perfusion Time Point Had No Obvious Effect on the Cerebrovasculature of saline-injected controls (Saline)-Injected Controls
This was supported by quantitative analysis, which detected no difference in fluorescein isothiocyanate (FITC)-LA labelling across the three time points
Summary
All protocols were approved by the University of Sydney Animal Ethics Committee Number 2017/1128, modification approved 20 September 2018). All experiments used male C57BL/6 mice, aged 12 weeks. Mouse weights ranged between 24 g and 30 g. Separate cohorts of mice were used for addressing the two aims of the study: the first cohort contained 28 mice and the second cohort contained 20 mice. Mice in the first cohort were randomly allocated to one of 8 experimental groups, corresponding to a specific time point post-injection at which they were sacrificed. Mice injected with MPTP were sacrificed at either 1 day (n = 4), 2 days (n = 4), 3 days (n = 4), 7 days (n = 4) or 14 days (n = 4)
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