A Role for Activated Microglia and Peroxynitrite in Lewy Body Diseases – Implications for Prevention and Control

Lewy body diseases – encompassing Parkinson’s disease, dementia with Lewy bodies, and Parkinson’s disease with late dementia – may reflect a vicious cycle of neuroinflammation in which aggregated alphasynuclein promotes microglial activation, and the peroxynitrite and cytokines produced by activated microglia in turn promote intraneuronal alpha-synuclein aggregation and neuronal death. If this model is correct, practical measures which dampen microglial activation and lessen peroxynitrite toxicity may aid the prevention and treatment of these disorders. Spirulina, a host of food polyphenols, DHA, astaxanthin, caffeine, a Mediterranean or plant-based diet, and exercise training have potential for blunting microglial activation. Measures which increase intraneuronal levels of urate and of glutathione – such as supplemental inosine, N-acetylcysteine, and phase 2 inducers – should mitigate the toxicity of peroxynitrite. Astaxanthin may suppress intraneuronal generation of superoxide and peroxynitrite by protecting the structure of mitochondrial inner membranes. Hence, it may eventually prove feasible to control or at least slow the progression of these devastating disorders with complex nutraceutical/lifestyle strategies. Synucleopathies – A Vicious Cycle of Microglial Activation and Neuronal Damage? The Lewy body diseases – a.k.a. synucleopathies, characterized by the intraneuronal and extraneuronal accumulation of protein aggregates rich in alpha-synuclein – include dementia with Lewy bodies (DLB), Parkinson’s disease (PD), and Parkinsons’s disease with late dementia (PDLD), seem likely to reflect a common pathogenetic mechanism that emerges initially in different parts of the brain – DLB in cortical regions, PD in the substantia nigra. But DLB is commonly complicated by Parkinsonian symptoms as it progresses, and PD patients are prone to progress to dementia. Hence, the synucleopathies tend to converge to a common clinical picture over time. Complicating the picture is the fact that dementias associated with Lewy bodies can be associated to a greater or lesser degree with amyloid beta-mediated pathology suggestive of Alzheimer’s disease. Despite the fact that DLB is now thought to be responsible for about 20% of dementing illness, there is essentially no epidemiology extant pertaining specifically to this disorder, and relatively few studies with transgenic mouse models overexpressing wild type or mutant alpha-synuclein have focused on cortical or cognitive function. Hence, efforts to postulate measures which might aid prevention or control of DLB might reasonably look to the ample research literature on PD for guidance – on the admittedly hypothetical but not unreasonable premise that the pathogeneses of DLB and PD are substantially homologous, differing primarily in the region of the brain that is first afflicted. On the basis of PD research, it is reasonable to suspect that Lewy body diseases are driven by a vicious cycle in which extracellular alpha-synuclein-rich protein aggregates, derived from necrotic neurons, promote the inflammatory activation of microglia, and the products of these microglia – peroxynitrite,