Preferential Heme Oxygenase-1 Activation in Striatal Astrocytes Antagonizes Dopaminergic Neuron Degeneration in MPTP-Intoxicated Mice

Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) accompanied by increased oxidative damage. Astrocytes, which are the most abundant glial cell types in the brain, possess higher antioxidant potential partially due to preferentially activated nuclear factor E2-related factor 2 genes. Heme oxygenase isoform 1 (HO-1) is crucial for the response to oxidative stress via the catabolism of heme to carbon monoxide, bilirubin, and iron. In the present study, we aimed to investigate astroglial expression of HO-1 in the SNpc, especially in the striatum of a subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mouse model of PD, and to investigate the neuroprotective effects of intraventricularly administrated HO-1 activator cobalt protoporphyrin IX (CoPPIX). The results showed that HO-1 was faintly distributed in neurons but not astrocytes in the normal SNpc and striatum. MPTP triggered a robust HO-1 response in the astrocytes of the striatum after 1-day treatment, but the HO-1 levels declined dramatically at day 3 and were completely undetectable at day 5. Intraventricular administration of CoPPIX for 8 days could preferentially activate HO-1 in astrocytes in the striatum but not SNpc. The content of striatal dopamine and its derivatives was restored in the subacute MPTP models. CoPPIX also increased the number of dopaminergic neurons and the tyrosine hydroxylase levels in the SNpc. These results suggest that inadequate HO-1 in striatal astrocytes might contribute to the limited antioxidant defense and dopaminergic neuron degeneration in PD, and preferential HO-1 activation in striatal astrocytes might be neuroprotective. The study thus sheds light on the targeting of HO-1 in striatal astrocytes for PD therapeutics.