harmine and Parkinsonian-Disorders

Parkinson's disease (PD) is a progressive neurodegenerative disorder that is a major public health concern due in part to prevalence, debilitating symptoms, and links to environmental exposures. Much research has focused on environmental factors that may lead to dopaminergic neurotoxicity that occurs in PD. In the study of neuronal uptake and neurotoxicity, critical species differences have been observed. For example, neuromelanin is a molecule formed in part by the breakdown products of dopamine metabolism, along with lipid and protein components. Interestingly, human catecholaminergic neurons contain readily detectable amounts of neuromelanin, while rodent models form far lower levels of neuromelanin that is barely detectable. This discrepancy is potentially an important translational weakness. Recently, we showed that neuromelanin formation modulates heterocyclic aromatic amine (HAA)-induced neurotoxicity in cellular models. HAAs are dietary toxins that have primarily been studied as carcinogens, with emergent literature on selective neurotoxicity. The goal of the present study was to identify whether mitochondria in neuromelanin forming cells may be especially sensitive to HAAs. Here, we exposed galactose-supplemented SH-SY5Y cells to HAAs and tested mitochondrial function and mitophagy. The ectopic formation of neuromelanin was found to increase mitochondrial oxidative stress, decrease membrane potential, increase mitochondrial bioenergetic impairments, and impair mitophagy relative to HAA-treated cells that do not form neuromelanin. These results suggest that neuromelanin has a critical role in HAA toxicity and adverse effects on mitochondria. The data also further cement the need to conduct both mechanistic and risk assessment studies on PD-relevant neurotoxicity in models that form neuromelanin.

Topics: Cell Line, Tumor; Energy Metabolism; Harmine; Humans; Imidazoles; Melanins; Membrane Potential, Mitochondrial; Mitochondria; Mitophagy; Neurons; Oxidative Stress; Parkinsonian Disorders

The effects of chemical products on the nervous system have been studied by various scientists. In this work, the antiparkinsonian action of a water-soluble form of harmine hydrochloride was studied. The present studies aim to research antiparkinsonian action of the harmine hydrochloride original compound.. To achieve the objective of the study, the authors used haloperidol-induced catalepsy and a method of Parkinson's syndrome (PS) induced by the MPTP (the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) neurotoxin. The experiments were performed on rats and mice which were divided into groups of 10 animals.. It was established that harmine hydrochloride (HH), at a certain dose, eliminated haloperidol-induced catalepsy in rats and reduced oligokinesia and rigidity in the parkinsonism test in mice. Seven days after the experiment, the authors found the presence of rigidity in animals which had received the neurotoxin. It manifested itself in a shortened stride length compared to this parameter in intact controls.. During the study the efficacy of harmine hydrochloride was equivalent to the effects of levodopa at a certain dose, which suggested that harmine hydrochloride compensated dopamine deficiency in the brain.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Antiparkinson Agents; Catalepsy; Haloperidol; Harmine; Levodopa; Male; Mice; Mice, Inbred C57BL; Parkinsonian Disorders; Rats

The beta-carboline norharman is present in cooked food and tobacco smoke and show structural resemblance to the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. C57BL/6 mice were injected subcutaneously with norharman (3 and 10 mg/kg) twice per day for five consecutive days. Eighteen hours after the last dose an increased expression of glial fibrillary acidic protein and fluoro-jade staining were demonstrated whereas the number of tyrosine hydroxylase positive cells were unchanged in the substantia nigra. Two weeks after the last treatment a decreased motor activity was observed whereas cognitive functions remained intact. In cultured PC12 cells norharman treatment induced mitochondrial dysfunction and increased the number of caspase-3 and TUNEL-positive cells. The results demonstrate that norharman induced apoptosis in cultured cells as well as early neurodegeneration, glial activation and sustained motor deficits in mice and suggest that exposure to norharman may contribute to idiopathic Parkinson's disease.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Apoptosis; Carbolines; Caspase 3; Caspases; Disease Models, Animal; Fluoresceins; Gait Disorders, Neurologic; Glial Fibrillary Acidic Protein; Gliosis; Harmine; Male; Maze Learning; Mice; Mice, Inbred C57BL; Mitochondria; Motor Activity; Nerve Degeneration; Neuroglia; Neurons; Neurotoxins; Organic Chemicals; Parkinsonian Disorders; PC12 Cells; Rats; Substantia Nigra