ABSTRACT
Objective The aim of this study was to establish a rat model of Parkinson''s disease ( PD) by using 6-hydroxydopamine (6-OHDA) and detect the salsolinol N-methyltransferase ( SNMT) activity in peripheral lymphocytes of PD rats for the development of a biomarker for early diagnosis of PD. Methods Rat model of PD was established by unilateral double-pointed injection of 6-OHDA into the striatum and was verified by behavior observation. An analytical method was developed based on multiple reaction monitoring with HPLC-ESI-QQQ to determine the SNMT activity in peripheral lymphocytes. Results Seven of 18 rats injected with 6-OHDA showed steadily apomorphine-induced rotation ( >7 r/min) . The success rate was 38. 9%. A sensitive and stable quantitative method with internal standard added was created, based on multiple reaction monitoring mode to analyze SNMT activity. The limit of detection ( LOD) and limit of quantitation ( LQD) of N-methyl-salsolinol, which is the product of Salsolinol catalyzed by SNMT, were 49 pmol/L and 98 pmol/L, respectively. The precisions of intra-day and inter-day assays both were below 6. 0%. SNMT activity of peripheral lymphocytes in the 6-OHDA-lesioned rats was significantly increased [43. 37 ±9. 49 pmol/(h·mg)NMSal] in comparison with that in the normal group [2. 16 ±5. 82 pmol/(h·mg)NMSal] and the sham-operated group [0. 58 ±2. 32 pmol/(h· mg)NMSal](P< 0. 01, n=5). There was no significant difference between the normal group and sham-operated group (P< 0. 05, n =5). Conclusions Our results indicate that SNMT activity may reflect the changes in the course of Parkison''s disease and may become a potential clinical biomarker in diagnosis of this disease.
ABSTRACT
Endogenous neurotoxin 1-methyl-6,7-dihydroxy-1,2,3,4 -tetrahydroisoquinoline (salsolinol, Sals), an endogenous dopamine metabolite, were shown to be toxic to dopaminergic neurons in vitro as well as in vivo, and was known to be involved in the pathogenesis of Parkinson's disease (PD). Sals is a more realistic model for selective toxicity to nigral dopaminergic neurons, and mimic the natural course of PD that develops slowly, allowing the brain to adapt to progressive damage. Sals lead to neurotoxicity in dopaminergic cells through induction of oxidative stress and apoptotic dopaminergic cell death, which made it as an important tool drugs to study the pathogenesis of PD.
ABSTRACT
Salsolinol, a dopamine-derived tetrahydroisoquinoline, is one of the endogenous alkaloids structurally related to morphine. It has been implicated in the pathophysiology of alcohol dependence and Parkinson's disease since it's first discovery in 1970's. Salsolinol is involved in many neurophysiological processes, including modulation of dopamine activity, facilitation of prolactin release and reinforcement of additive substance craving. In addition, salsolinol exerts highly neurotoxic effects on dopaminergic neurons ultimately leading to apoptosis, which is mediated by inhibition of endogenous antioxidants and, thereby, production of reactive oxygen species (ROS). These properties are considerably based in alcohol dependence and several neurodegenerative disorders including Parkinson's disease. Salsolinol is synthesized by the condensation of dopamine with acetaldehyde or pyruvate through enzymatic or non-enzymatic processes in the dopamine-rich neurons. Acute alcohol ingestion increase the level of acetaldehyde and salsolinol is structurally related to endogenous opioids. Therefore, it has been suggested that salsolinol may be the missing link between alcohol ingestion and the activation of reward pathway in the mesolimbic brain. The reinforcing effect of both alcohol and salsolinol in self-administration setting also strongly supports this hypothesis. N-methylsalsolinol, the major metabolite of salsolinol, is highly neurotoxic and responsible for the selective destruction of dopaminergic neurons in Parkinson's disease. In contrast to this, several structural analogs of salsolinol act as endogenous anti-parkinsonism substances. Delicate structural differences may underlie this peculiar properties. It may become possible to introduce fine structural modifications, even stereo-specific manipulations, to develop entirely newer kinds of antiparkinsonism drugs. Although the implication of salsolinol in the pathophysiology of alcohol dependence had been suggested long ago, the progression of the related research was at most very limited up to now. Even now, this important chemical, deeply involved in a wide range of essential neurophysiological processes, still is relatively neglected by psychiatric researchers. However, it is expected that the accumulating knowledge of salsolinol's neuromodulatory and neurotoxic effects will give new insights into the many dopamine related psychiatric disorders including substance dependence, parkinsonism and schizophrenia. We expect that many psychiatrists will give proper attention to this highly promising research subject.