Will it Ever Become Possible to Prevent Dopaminergic Neuronal Degeneration?

Abstract

Abstract:Parkinson's disease (PD) is the second leading age-related degenerative brain disease in the world affecting millions of people. This neurological disorder disrupts the quality of life of patients and their families, exerts an enormous emotional and physical strain on caregivers, and has a large cost for society. Moreover, the increasing numbers of elderly people in the population will result in a sharp increase in the prevalence of PD. The understanding of its pathophysiology and treatment has advanced at a very impressive rate during past decades. Nevertheless, PD is still fatal and there is at present no cure for it. Furthermore, there are no proven therapies for prevention of PD and although evidence exists of risk and protective factors, this is not strong enough to warrant specific measures in an attempt to diminish risk or enhance protection. Drug development programmes are engaged in finding neuroprotective and neurorestorative therapies or, even better, discovering drugs able to rejuvenate the dopaminergic neurons. The latest developments in this promising field will be discussed with reference to the current literature together with the advantages and pitfalls of suggested drugs. Finally, an analysis of the role of various dietary recommendations, lifestyle, environmental and other factors in reducing the risk of PD is carried out.

Nitric Oxide Modulation of the Basal Ganglia Circuitry: Therapeutic Implication for Parkinson's Disease and Other Motor Disorders

“…The role of oxidative stress in the pathogenesis of MPTP/MPP + -induced DAergic degeneration, has been suggested [56,58,61,[139][140][141]147]. Numerous studies have proposed that nNOS inhibitors, including 7-NI, may reduce DAergic neuronal degeneration, both in vitro and in vivo through antioxidative mechanisms [148][149][150]. The neuroprotective effect of 7-NI against MPP + -induced DA striatal depletion is probably due to a block in the rise of the toxic NO 3¯ produced by the combination of NO and ˙OH induced by MPP + , as shown in previous studies [142,151].…”

“…The increased DA turnover could itself enhance basal production of hydrogen peroxide and cause a depletion of reduced glutathione stores, leading to further overproduction of toxic ˙OH, as a consequence of impaired glutathione scavenging activity. Thus, PD aetiology could be explained by a genetic susceptibility to environmental or endogenous agents leading to oxidative damage in a neuronal population that is naturally under oxidative stress [149]. However, other mechanisms by which 7-NI modifies the effects of 6-OHDA cannot be ruled out.…”

Serotonin–dopamine interaction: an overview

“…In the future, the use of such selective ligands, especially agonists of 5-HT receptors, would certainly be helpful in determining their functional importance and their involvement in the pathogenesis of diseases, not exclusively of the CNS. This has a particular relevance for those disorders such as Parkinsons's disease that are still fatal and for which at present there is no cure (Esposito et al, 2007;Di Giovanni, 2008). However, it should be kept in mind that although selective receptor ligands are an important and indispensable research tool, they rarely happen, in practice, to be drugs.…”

Serotonin modulation of the basal ganglia circuitry: therapeutic implication for Parkinson's disease and other motor disorders

“…Hitherto, the underlying mechanisms of neuronal loss in patients are not known. Therefore, current therapies work mainly to alleviate symptoms rather than to halt the progression of the disease (Di Giovanni, 2008). There have been major advances in understanding the aetiopathogenesis of PD and the modalities whereby the neurodegenerative process begins and progresses; therefore, the development of drugs to slow and halt DAergic neuronal degeneration or even to prevent the disease now seems realistic (Esposito et al, 2007a, b, c;Di Giovanni, 2008).…”