Objective: To examine whether the variable sensitivity of dopaminergic neurons of the substantia nigra pars compacta -SNpc- in C57BL/6J and CD-1 mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/ MPTP is governed by glia through their specific molecular properties.

Background: Both astroglia and microglia show region-specific distribution in CNS and often show reactive phenotypes to age-associated alterations. Studies on autopsied SN of Parkinson disease (PD) patients and experimental models propose gliosis as a point-of-initiation for neuronal deficits. Besides, epidemiological studies propose an ethnic bias in PD prevalence, since Caucasians are more susceptible than non-whites. Since different mice strains are variably sensitive to MPTP, we had earlier equated variable MPTP-sensitivity of C57BL/6J and CD-1 mice with variable susceptibility to PD, based on the numbers of SN neurons.

Method: Astroglia and microglia were identified by S100b and IBA-1 labeling respectively and quantified by stereology. A panel of pro- and anti-inflammatory cytokines was assessed by ELISA and few other proteins by immunoblotting. Ultrastructural changes were examined by transmission electron microscopy.

Results: Stereological quantification showed relatively larger number of microglia and fewer astrocytes in the SN of normal C57BL/6J mice, suggesting persistence of an immune-vigilant state. MPTP caused microgliosis and astrogliosis in both strains, hinting at their involvement in pathogenesis. ELISA of pro-inflammatory cytokines in ventral-midbrain revealed augmentation of TNF-α and IL-6 at middle-age in both strains, that reduced at old-age, suggesting middle-age as a critical, inflamm-aging associated time-point. TNF-α levels were high in C57BL/6J, through aging and post-MPTP; while IL-6 and IL-1β were increased at old-age. CD-1 had high levels of anti-inflammatory cytokine TGF-β. MPTP upregulated enzymes MAO-A, MAO-B and iNOS in both strains. MPTP-induced increase in fractalkine and hemeoxygenase-1; may be neuron-associated compensatory signals. Ultrastructural observations of elongated astroglial/microglial mitochondria vis-à-vis the shrunken ones in neurons, suggest a scale-up of their functions with neurotoxic consequences.

Conclusion: Both, astroglia and microglia may moderate aging and vulnerability to Parkinson disease.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/differences-in-molecular-and-ultrastructural-profiles-of-astroglia-and-microglia-in-substantia-nigra-of-two-different-mice-strains-in-normal-aging-and-experimental-parkinsonism/