Dopaminergic Neurotoxicity In Vivo and Inhibition of Mitochondrial Respiration In Vitro by Possible Endogenous Pyridinium‐Like Substances

Abstract

Elucidation of the mechanism(s) by which 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) and its active metabolite 1-methyl-4-phenylpyridinium (MPP+) cause parkinsonism in humans and other primates has prompted consideration of possible endogenous MPTP/MPP(+)-like neurotoxins in the etiology of idiopathic Parkinson's disease. Here we examined inhibition of mitochondrial respiration in vitro and neurotoxicity in rats in vivo produced by beta-carbolinium compounds that are presumed to form following Pictet-Spengler cyclization of serotonin. We also evaluated N-methylisoquinolinium, a putative endogenous neurotoxin, in the same manner. The latter compound exhibited MPP(+)-like mitochondrial respiratory inhibition, whereas the beta-carbolinium compounds, although more potent inhibitors of electron transport, exhibited weak accumulation-dependent enhancement of inhibition in intact mitochondria. It is interesting that the beta-carbolinium compounds inhibited succinate- as well as glutamate-supported respiration, and are best described as inhibitor-uncouplers. The results of partitioning experiments suggest that both the low accumulation potential and the inhibition of succinate respiration may be a consequence of the beta-carboliniums being in equilibrium with neutral "anhydro" bases. Relative to MPP+, all compounds tested had weak dopaminergic uptake activity in vitro and weak dopaminergic toxicity in vivo, consistent with other findings of relatively low neurotoxic potential for presumed endogenous pyridiniums.

Advanced Maillard reaction end products are associated with Alzheimer disease pathology.

“…To assess the specificity of the pentosidine antisera we synthesized a selection of candidate "cross-reactive" compounds. 1-Methyl-4-(2,5-dimethylpyrrolylmethyl)pyridinium iodide (13), 1-methyl-4-(5-methylfuran-2-yl)pyridiniumiodide(13),1-methyl-4-(4-hydroxyphenoxy)pyridinium iodide (13), N-methylisoquinolinium iodide (14), 6-hydroxy-2-methylnorharmanium bromide (14), and pentosidine (9) were described in previous studies. trans-2-Buten-1,4-yl-bis(3-hydroxypyridinium) dichloride was prepared by heating a 2:1 molar mixture of 3-hydroxypyridine and further condensation reactions result in the formation of a wide array of advanced Maillard reaction end products, including pyrroles (e.g., pyrraline) and imidazopyridiniums (e.g., pentosidine).…”

Elevated levels of harman and norharman in cerebrospinal fluid of Parkinsonian patients

“…[3-carbolines, like harman and norharman, show structural resemblance to MPTP and its ion MPP + (Neafsay et al, 1989;Sayre et al, 1990). In vivo they may easily be formed by cyclization of indoleamines with e.g.…”

“…The potent neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces cell death in dopaminergic neurons (Sayre et al, 1990). [3-carbolines, like harman and norharman, show structural resemblance to MPTP and its ion MPP + (Neafsay et al, 1989;Sayre et al, 1990).…”

“…In vivo they may easily be formed by cyclization of indoleamines with e.g. aldehydes (Neafsay et al, 1989;Sayre et al, 1990). Therefore several studies were initiated to elucidate the potential neurotoxicity of these compounds.…”

Literature review and appraisal on alternative neurotoxicity testing methods

“…The 9 false negative data for the endpoint category 'mitochondrial dysfunction/oxidative stress/apoptosis' in isolated organelles include rat brain as well as liver mitochondria. Here, lack of effect on oxygen consumption (Sayre et al, 1991), ROS formation (Fonck & Baudry, 2003), protein or lipid oxidation (Taskiran et al, 2007) were the reasons for categorization. Rat brain or liver mitochondria have 37.5% and 100% false negative rate.…”