1-Methyl-1,2,3,4-Tetrahydroisoquinoline, an Endogenous Amine with Unexpected Mechanism of Action: New Vistas of Therapeutic Application

Abstract

This review outlines the effects of 1,2,3,4-tetrahydroisoquinoline (TIQ) and its derivative, 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ), endogenous substances imbued with high pharmacological potential and broad spectrum of action in brain. 1MeTIQ has gained special interest as a neuroprotectant, and its ability to antagonize the behavioral syndrome produced by well-known neurotoxins (e.g., MPTP; rotenone). This review is thus focused on mechanisms of action of 1MeTIQ in behavioral, neurochemical, and molecular studies in rodents; also, effects of TIQ and 1MeTIQ on dopamine metabolism; and neuroprotective properties of TIQ and 1MeTIQ in vitro and in vivo. Finally, antiaddictive properties of 1MeTIQ will be described in cocaine self-administered rats. Findings implicate TIQ and especially its methyl derivative 1MeTIQ in unique and complex mechanisms of neuroprotection in various neurodegenerative illnesses of the central nervous system. We believe that MAO inhibition, free radicals scavenging properties, and antagonism to the glutamatergic system may play an essential role in neuroprotection. In addition, the results strongly support the view that 1MeTIQ has a considerable potential as a drug for combating substance abuse, through the attenuation of craving.

Neuroprotective Effect of the Endogenous Amine 1MeTIQ in an Animal Model of Parkinson’s Disease

“…As an endogenous inhibitor of MAO activity, 1MeTIQ shifts DA catabolism toward COMT-dependent O -methylation, thereby increasing the concentration of the extraneuronal DA metabolite, 3-MT (Antkiewicz-Michaluk et al 2001 ; Patsenka and Antkiewicz-Michaluk 2004 ). Indeed, we previously observed that 1MeTIQ possesses neuroprotective activity in different animal models of neurodegeneration and protects neurons against glutamate- and kainite-induced excitotoxicity (Antkiewicz-Michaluk et al 2006 , 2014 ).…”

“…Notably, the development of tolerance after the repeated administration of 1MeTIQ was not observed. This effect of 1MeTIQ can be explained by two mechanisms: (1) As a partial dopamine agonist, 1MeTIQ could block the active conformation of the DA receptor (Antkiewicz-Michaluk et al 2014 ); and (2) 1MeTIQ shifts DA catabolism toward COMT-dependent O -methylation pathway, thereby significantly increasing the extraneuronal metabolite concentration of 3-MT (Antkiewicz-Michaluk et al 2001 ). Moreover, 3-MT shows affinity to the α-adrenergic receptor as an antagonist, and this molecule might play an important physiological role as an inhibitory regulator, counteracting the excessive stimulation of catecholaminergic neurons (Antkiewicz-Michaluk et al 2008 ).…”

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

“…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 ). These researches have suggested that 1-MeTIQ possesses high affinity for brain tissue acting as partial DA agonist, reversibly reducing, both in vitro and in vivo, MAO-A and MAO-B activities, inhibiting more potently MAO-A than MAO-B (Patsenka and Antkiewicz-Michaluk 2004).…”

“…Therefore, 1-MeTIQ as an endogenous neuroprotective compound, with a different antidepressant-like activity in rodents, could be an effective antidepressant drug for future therapeutic use . Moreover, direct and indirect evidence indicates that 1-MeTIQ could be a potential antiparkinsonian drug on the basis of its ability to reduce MPTP-induced bradykinesia ) and a potential drug useful for treating drug abuse, based on its ability to decrease craving as reported by Antkiewicz-Michaluk's research group (Antkiewicz-Michaluk 2002;Antkiewicz-Michaluk et al 2014). A recent in vivo microdialysis investigation also demonstrated that multiple treatments with both endogenous amines, as TIQ and 1-MeTIQ, protect DAergic neurons against a 6-OHDA-induced reduction of DA release (Wąsik et al 2018a).…”

1metiq, an Endogenous Compound Present in the Mammalian Brain Displays Neuroprotective, Antiaddictive and Antidepressant-Like Activity in Animal Models of theCentral Nervous System Disorders

“…In all of the above introduced animal models of depression, both investigated compounds (TIQ and 1MeTIQ) completely antagonized behavioral and neurochemical syndromes of depressive-like behavior in rodents displaying therapeutic potential similar to a classical antidepressant, imipramine [59,88,89].…”