Abstract
1-Benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ) was shown to be neurotoxic to the dopaminergic neurons, and thus it was proposed to be an endogenous risk factor leading to Parkinson’s disease. In order to better understand the molecular mechanisms of 1BnTIQ—produced toxicity, we examined the impact of different concentrations of 1BnTIQ (50, 100, and 500 μM) on glutamate-induced apoptotic pathway. We measured the markers of apoptosis, such as caspase-3 activity, lactate dehydrogenase release, and mitochondrial membrane potential. Molecular data were supported at the cellular level by calcein AM and Hoechst 33342 staining. The obtained data demonstrated concentration-dependent effects of 1BnTIQ opposing apoptosis, and evidenced that 1BnTIQ in a low concentration (50 μM) exhibited neuroprotective activity, whereas in 10 times higher concentration (500 μM) might be neurotoxic, and significantly intensified glutamate-induced increase in apoptosis markers. Additionally, using an ex vivo molecular study we indicated that both acute and chronic administration of 1BnTIQ did not affect the level of alpha synuclein and tyrosine hydroxylase protein in the rat substantia nigra. Summarizing the studies, we suggest that 1BnTIQ is a rather weak endogenous neurotoxin; however, it should be taken into account that in higher μmoles concentrations, it can initiate apoptosis in the central nervous system and may be involved in the etiopathology of neurodegenerative diseases.
Highlights
The programed cell death is a biological process in which unwanted and/or damaged cells are killed, so that the organism could maintain homeostasis
In hippocampal cultures exposed to 1 mM glutamate for 24 h, the activity of caspase-3 increased by 30 % (p \ 0.001) (Fig. 1)
The main finding of this paper is that 1BnTIQ produced concentration-dependent opposite effects on markers of apoptosis evaluated by in vitro studies in primary hippocampal cultures of the mouse and the rat. 1BnTIQ in a low concentration (50 lM) possessed neuroprotective activity, while in a 10 times higher concentration (500 lM) might be neurotoxic, and significantly intensified glutamateinduced neurotoxicity
Summary
The programed cell death (apoptosis) is a biological process in which unwanted and/or damaged cells are killed, so that the organism could maintain homeostasis. The apoptosis process is a characteristic of normal development and of numerous neurodegenerative diseases and neurological conditions, such as Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease, and stroke (Bamberger and Landreth 2002; Jenner 2003; Mattson 2003; McLaughlin et al 1998; Morishima et al 2001). Keep in mind that in the neurodegenerative diseases, neuronal cells death occurs via apoptosis and in the necrosis. Apoptosis mainly affects the cell nucleus and is related to specific DNA fragmentation which results in apoptotic body formation and individual cell death without inflammatory response to damage (Honda et al 2001). Apoptosis is regulated by the activation of the caspase cascade, which depends on nonspecific insults leading to calcium influx into the cytoplasm and reduction of mitochondrial membrane potential
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