Reply: a new look at the pathogenesis of Parkinson's disease

We are grateful to Drs Hirsch and Hunot for their insightful comments on our work1xInducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease. Liberatore, G.T. et al. Nat. Med. 1999; 5: 1403–1409Crossref | PubMed | Scopus (709)See all References1 and for their thorough review of the potential role of gliosis and inflammatory-related events in the pathogenesis of Parkinson’s disease (PD). We wish to echo Drs Hirsch and Hunot’s view on the importance of this long-neglected aspect of PD neuropathology2xReactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. McGeer, P.L. et al. Neurology. 1988; 38: 1285–1291Crossref | PubMedSee all References, 3xNitric oxide synthase and neuronal vulnerability in Parkinson’s disease. Hunot, S. et al. Neuroscience. 1996; 72: 355–363Crossref | PubMed | Scopus (406)See all References, 4xFcϵRII/CD23 is expressed in Parkinson’s disease and induces, in vitro, production of nitric oxide and tumor necrosis factor-α in glial cells. Hunot, S. et al. J. Neurosci. 1999; 19: 3440–3447PubMedSee all References. Furthermore, we would like to stress a point that can be derived from the work of Hirsch and Hunot as well as from our own, which we believe might have significant therapeutic implications for PD.Almost invariably, the phenotypic expression of neurodegenerative disorders such as PD arises in a specific part of the body (e.g. upper limb, on one side) and then spreads progressively. This fact led us to hypothesize that once the neurodegenerative process has been initiated by the aetiological factor(s), a cascade of secondary deleterious events that is instrumental in the progression and propagation of the disease is set in motion. As we have emphasized1xInducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease. Liberatore, G.T. et al. Nat. Med. 1999; 5: 1403–1409Crossref | PubMed | Scopus (709)See all References1, our data indicate that the contribution of inducible nitric oxide synthase (iNOS) and gliosis-related deleterious effects to the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD do not initiate the loss of dopamine-containing neurones, but rather amplify the damage in MPTP-intoxicated mice. Dopaminergic fibres and dopamine content in the striatum were not spared from the toxic effects of MPTP in iNOS knockout mice, which differs from that observed in neuronal NOS (nNOS) knockout mice, in which dopamine and its metabolites are spared from the toxic effects of MPTP (Ref. 5xRole of neuronal nitric oxide in MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced dopaminergic neurotoxicity. Przedborski, S. et al. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 4565–4571Crossref | PubMedSee all ReferencesRef. 5). Thus, MPTP might elicit its toxicity by nNOS-derived nitric oxide (NO) damaging primarily dopaminergic fibres and terminals in the striatum and iNOS-derived NO acting predominately on dopamine-containing neuronal cell bodies in the substantia nigra pars compacta. Injury induced by neuronally derived NO might serve as the catalyst to activate iNOS and gliosis-related deleterious effects. A similar scenario might apply to the demise of dopamine-containing neurones in humans either affected with PD (2xReactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. McGeer, P.L. et al. Neurology. 1988; 38: 1285–1291Crossref | PubMedSee all References, 3xNitric oxide synthase and neuronal vulnerability in Parkinson’s disease. Hunot, S. et al. Neuroscience. 1996; 72: 355–363Crossref | PubMed | Scopus (406)See all References, 4xFcϵRII/CD23 is expressed in Parkinson’s disease and induces, in vitro, production of nitric oxide and tumor necrosis factor-α in glial cells. Hunot, S. et al. J. Neurosci. 1999; 19: 3440–3447PubMedSee all References) or intoxicated by MPTP (Ref. 6xEvidence of active nerve cell degeneration in the substantia nigra of humans years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure. Langston, J.W. et al. Ann. Neurol. 1999; 46: 598–605Crossref | PubMed | Scopus (567)See all ReferencesRef. 6).Aside from providing insights into the factors that contribute to the progression of the neurodegenerative process in PD, studies on inflammatory-related events shed light on new therapeutic avenues. Thus far, the lion’s share of these avenues has been therapeutic interventions aimed at alleviating symptoms of PD. Unfortunately, the chronic use of potent symptomatic anti-PD drugs is frequently wrought with long-term side-effects, which are as debilitating as the disease itself. Moreover, in the vast majority of cases, PD presents as a sporadic disease. Thus, in the absence of pre-symptomatic markers, PD patients seek medical attention at a time when they are already symptomatic. Consequently, therapeutic interventions that target secondary phenomenon such as iNOS induction and gliosis might represent a promising strategy that could succeed in slowing down or even stopping the progression of PD. Ultimately, the cause of PD must be unravelled and therapeutic strategies aimed at preventing the illness must be developed. But, for now our best therapeutic alternative probably lies in targeting secondary neurodegenerative processes.