Effects of 1,2,3,4-Tetrahydroisoquinoline Derivatives on Dopaminergic Spontaneous Discharge in Substantia Nigra Neurons in Rats

Abstract

1,2,3,4-Tetrahydroisoquinoline (TIQ) and its derivatives, 1-methyl-TIQ (1-MeTIQ) and 1-benzyl-TIQ (1-BnTIQ), are endogenously present in the human brain. In this study, we compared the effects of TIQ derivatives on spontaneous nigral dopaminergic discharge in rats treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In the low-to-middle dose range (0.01-1 mg/kg), intravenous administration of MPTP induced a transient and potent increase in the firing rate. TIQ (0.01-30 mg/kg) had no effects, and 1-MeTIQ and 1-BnTIQ (0.01-10 mg/kg) produced a weaker increase in the firing frequency immediately after intravenous administration. Pretreatment with 1-MeTIQ (80 mg/kg, i.p.) significantly inhibited the decrease in dopaminergic spontaneous firing induced by a high dose of MPTP. The nigral induction of thiobarbituric acid-reactive substances (TBARS) by MPTP was also significantly suppressed by pretreatment with 1-MeTIQ. These results suggest that the neurotoxicity induced by TIQ derivatives is relatively weak compared to that induced by MPTP. The neuroprotective effect of 1-MeTIQ from MPTP-induced toxicity may be partially due to a decrease in free radicals, as suggested by a decrease in TBARS. This action presumably prevents cell membrane degeneration.

Not Just from Ethanol. Tetrahydroisoquinolinic (TIQ) Derivatives: from Neurotoxicity to Neuroprotection

“…A great deal of the experimental evidence demonstrates that oxidative stress is a principal reason of cell death and that an abnormal concentration of reactive oxygen and nitrogen species leads to the damage of a lot of lipids, proteins and also DNA. As reported by Antkiewicz-Michaluk and collaborators (Antkiewicz-Michaluk et al 2014), 1-MeTIQ possesses neuroprotective actions, probably attributable to its ability to reduce oxidative stress Wąsik and Antkiewicz-Michaluk 2017) by free radicals scavenging, prevention of cell membrane deterioration and glutamate-induced excitotoxicity inhibitory events Chiba et al 2015). Antkiewicz-Michaluk et al (2014) also demonstrated that 1-MeTIQ through MAO inhibition might play an essential role in neuroprotection confirming the important role of catecholamines in the formation of TIQs ).…”

“…Most of the TIQs found in the brain are nowadays commonly recognized as endogenous neurotoxins with neurochemical properties similar to those of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), the also structurally similar compound most famous for causing Parkinson's disease (PD) (Herraiz 2016). Interestingly, as it occurs with MPTP, important differences may be related to the enzymes involved in the mechanisms of toxicity (Herraiz 2016); in particular, TIQs can be metabolically activated by conversion into potentially toxic substances, although one of the most striking differences with respect to MPTP refers to the fact that TIQsinduced neurotoxicity is relatively weaker compared to that induced by MPTP (Chiba et al 2015). Notably, MPTP and its oxidation by-product, 1-methyl-4-phenylpyridinium cation (MPP + ), are selective DArgic neurotoxins that when administered directly into the mice brain induce neuronal degeneration that can provide the experimental animal models of parkinsonism extensively used to investigate the mechanisms underlying neurotoxicity and neurodegeneration as well as to find drugs able to exert neuroprotective effects against oxidative stress-mediated neurotoxicity (Chiueh et al 1984;Jackson-Lewis and Przedborski 2007).…”