The biochemical and cellular basis for nutraceutical strategies to attenuate neurodegeneration in Parkinson's disease

Abstract

Future therapeutic intervention that could effectively decelerate the rate of degeneration within the substantia nigra pars compacta (SNc) could add years of mobility and reduce morbidity associated with Parkinson's disease (PD). Neurodegenerative decline associated with PD is distinguished by extensive damage to SNc dopaminergic (DAergic) neurons and decay of the striatal tract. While genetic mutations or environmental toxins can precipitate pathology, progressive degenerative succession involves a gradual decline in DA neurotransmission/synaptic uptake, impaired oxidative glucose consumption, a rise in striatal lactate and chronic inflammation. Nutraceuticals play a fundamental role in energy metabolism and signaling transduction pathways that control neurotransmission and inflammation. However, the use of nutritional supplements to slow the progression of PD has met with considerable challenge and has thus far proven unsuccessful. This review re-examines precipitating factors and insults involved in PD and how nutraceuticals can affect each of these biological targets. Discussed are disease dynamics (Sections 1 and 2) and natural substances, vitamins and minerals that could impact disease processes (Section 3). Topics include nutritional influences on α-synuclein aggregation, ubiquitin proteasome function, mTOR signaling/lysosomal-autophagy, energy failure, faulty catecholamine trafficking, DA oxidation, synthesis of toxic DA-quinones, o-semiquinones, benzothiazolines, hyperhomocyseinemia, methylation, inflammation and irreversible oxidation of neuromelanin. In summary, it is clear that future research will be required to consider the multi-faceted nature of this disease and re-examine how and why the use of nutritional multi-vitamin-mineral and plant-based combinations could be used to slow the progression of PD, if possible.

Keywords: Parkinson’s disease; neuromelanin; neuroprotective; nutrition; vitamins.

Figure 1

PET Imaging Tools Used in PD. Schematic representation of dopamine synthesis and metabolism, including sites of action of pre-synaptic dopaminergic PET ligands. (1) FD reflects uptake of l-dopa, the AADC activity, and the storage of dopamine in pre-synaptic vesicles; (2) MP binds to the dopamine transporter, which is specific for the gradient-determined re-uptake of dopamine; and (3) DTBZ binds to vesicular monoamine transporter type 2, which is responsible for the uptake of monoamines into pre-synaptic vesicles. In the striatum, more than 95% of the monoaminergic nerve terminals are dopaminergic. (AADC: aromatic amino acid decarboxylase; COMT: catechol-O-methyltransferase; DOPAC: 3,4-dihydroxyphenylacetic acid; DTBZ: ^[11C]-dihydrotetrabenazine; FD: 6-^[18F]-fluoro-ldopa; HVA: homovanillic acid; l-DOPA: l-3,4-dihydroxyphenylalanine; MAO: monoamine oxidase; MP: ^[11C]-d-threomethylphenidate; 3-MT: 3- methoxytyramine; TH: tyrosine hydroxylase) [30].

Figure 2

Imaging dopamine terminal function in healthy controls and early Parkinson’s disease (Modified from [28]).

Figure 3

Melanized dopaminergic neurons of the substantia nigra from post mortem human brain. Brain sections taken through the mid- brain of a normal (left) and a Parkinson’s disease patient (right). The Parkinson’s diseased hemisphere on the right shows a loss of the melanized neurons in the substantia nigra in the ventral midbrain [137].

Figure 4

In the PD patient (A and B), binding is increased in the basal ganglia, pons and frontal regions, while the healthy control person (C and D) only shows constitutive [11C] (R)-PK11195 binding in the thalamus and pons. The color bar denotes binding potential values from 0 to 1 [227].