Agnieszka Wąsik

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

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.

Antidepressant-like activity of the endogenous amine, 1-methyl-1,2,3,4-tetrahydroisoquinoline in the behavioral despair test in the rat, and its neurochemical correlates: A comparison with the classical antidepressant, imipramine

Disturbances in noradrenergic and serotonergic transmissions have been postulated to form neurochemical background of depression. 1-Methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) is an endogenous substance which exhibits neuroprotective, antiaddictive and monoamine oxidase (MAO)-inhibiting properties. In the present study, we tested antidepressant-like effects of 1MeTIQ in comparison with the tricyclic antidepressant, imipramine in the forced swimming test in the rat. Additionally, in neurochemical studies, we estimated the rate of monoamine (dopamine, noradrenaline and serotonin) metabolism in the rat brain structures. The findings have shown that 1MeTIQ similarly to imipramine produced a dose-dependent antidepressant-like effect in the forced swimming test. The neurochemical data showed that 1MeTIQ produced a significant elevation of serotonin concentration in the brain structures with simultaneous reduction of its metabolite, 5-hydroxyindoleacetic acid (5-HIAA). Moreover, 1MeTIQ slightly increased noradrenaline level but induced a significant elevation of its metabolite, 3-metoxy-4-hydroxyphenylglycol (MHPG). Furthermore, 1MeTIQ affected also dopamine metabolism, and decreased the level of 3,4-dihydroxyphenylacetic acid (DOPAC) with a simultaneous significant increase in the concentration of 3-methoxytyramine (3-MT) in all investigated structures. Such mechanism of action leads to a decrease in the production of free radicals during MAO-dependent dopamine oxidation in the brain. In conclusion, we suggest that antidepressant-like activity of 1MeTIQ is based on the unique and complex mechanism of action in which the activation of monoaminergic systems and scavenging of free radicals plays a crucial role. 1MeTIQ as an endogenous compound may be beneficial from the clinical point of view as a new safer and more efficient antidepressant.

Effects of perinatal exposure to lead (Pb) on purine receptor expression in the brain and gliosis in rats tolerant to morphine analgesia.

The aim of the present study was to investigate the molecular effects of perinatal exposure to lead (Pb) on protein and mRNA expression of purine receptors: P2X4, P2X7, adenosine receptor A1; and astrocytes (GFAP mRNA expression) and on microglia activation (Iba1 mRNA expression) in several structures of the mesolimbic system (striatum, hippocampus, prefrontal cortex) in rats expressing tolerance to the antinociceptive effect of morphine. Rat mothers were orally treated with 0.1% lead acetate from conception, through gestation, and postnatally, as well as to offspring up to day (PND) 28; subsequently molecular studies were conducted on adult (PND 60) male rats. Morphine tolerance developed more strongly in rats perinatally exposed to Pb. The analysis revealed a significant up-regulation of protein and mRNA P2X4 receptor expression in the striatum and prefrontal cortex but not in the hippocampus; P2X7 protein and mRNA receptor expression in the striatum and hippocampus, but not in the prefrontal cortex; A1 protein receptor expression in all investigated structures and A1 mRNA expression in the striatum and hippocampus; Iba1 mRNA expression in the striatum and hippocampus; and GFAP mRNA expression in the striatum and prefrontal cortex. Immunohistochemical analysis has also revealed significant alterations. Strong expressions of P2X4, P2X7, A1 receptors, astrocytes and microglia activation were observed in the hippocampus in Pb and/or morphine treated rats. The higher expression of purine receptors and glial cell activation are important markers of neuroinflammatory processes. Therefore, we conclude that Pb-induced neuroinflammation may be responsible for the intensification of morphine tolerance in the Pb-treated rats. Additionally, the dysregulation of A1 adenosine receptors, mainly in the hippocampus, may also be involved in the intensification of morphine tolerance in Pb-treated rats. Our study demonstrates the significant participation of environmental factors in addictive process; additionally, it shows the necessity of modification of addictive disorder with neuroprotective agents.

1,2,3,4-Tetrahydroisoquinoline produces an antidepressant-like effect in the forced swim test and chronic mild stress model of depression in the rat: Neurochemical correlates.

1,2,3,4-Tetrahydroisoquinoline (TIQ) is an exo- and endogenous amine naturally present in mammalian brain which displays antidepressant-like effect in various animal models: the forced swim test (FST) and chronic mild stress (CMS) paradigm in rats. To elucidate this action we compared the effects of TIQ with imipramine, a classic antidepressant drug and one of the most clinically effective. Applied behavioral tests showed that TIQ produced an antidepressant-like effect with a potency comparable to that of imipramine. TIQ (25-50mg/kg i.p.), similarly to imipramine (10-30mg/kg i.p.), reduced the immobility time in FST and completely reversed the decrease in sucrose intake caused by CMS in the rat. In addition, in order to avoid the possible psychostimulating effect of TIQ we examined the influence of its administration on locomotor activity in rats. TIQ, like imipramine, produced a reduction in horizontal locomotor activity. This suggested that TIQ did not have psychostimulant properties and that prolonged swimming in the FST was a result of an increased motivation to escape from the stressful situation. The biochemical analyses have shown that TIQ activates monoaminergic systems as a reversible monoamine oxidase (MAO) inhibitor and free radical scavenger. Beyond the activation of noradrenaline and serotonin systems, TIQ also moderately affects the dopamine system. On the basis of the presented behavioral and biochemical studies we suggest that TIQ is a potential new antidepressant which may be effective for the depression therapy in a clinical setting.

The mechanism of neuroprotective action of natural compounds

Disturbance of cerebral redox homeostasis is the primary cause of human neurodegenerative disorders, such as Parkinsons disease or Alzheimers disease. Well known experimental research demonstrates that oxidative stress is a main cause of cell death. A high concentration of reactive oxygen and nitrogen species leads to damage of a lot of proteins, lipids and also DNA. Synthetic compounds used for the treatment in the neurodegenerative diseases failed to meet the hopes they had raised and often exhibit a number of side effects. Therefore, in recent years interest in natural compounds derived from plants appears to be on the rise. This review describes a few natural compounds (1MeTIQ, resveratrol, curcumin, vitamin C and Gingko biloba) which revealed neuroprotective potential both in experimental studies and clinical trials. 1MeTIQ has a privileged position because, as opposed to the remaining compounds, it is an endogenous amine synthesized in human and animal brain. Based on evidence from research, it seems that a common protective mechanism for all the above-mentioned natural compounds relies on their ability to inhibit or even scavenge the excess of free radicals generated in oxidative and neurotoxin-induced processes in nerve cells of the brain. However, it was demonstrated that further different molecular processes connected with neurotoxicity (e.g. the inhibition of mitochondrial complex I, activation of caspase-3, apoptosis) follow later and are initiated by the reactive oxygen species. What is more, these natural compounds are able to inhibit further stages of apoptosis triggered by neurotoxins in the brain.

1-Methyl-1,2,3,4-tetrahydroisoquinoline, an endogenous Neuroprotectant and MAO inhibitor with antidepressant-like properties in the rat.

Oxidative stress is a major contributing factor in a range of brain pathologies and in the etiology of depression. 1-Methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) is an endogenous substance which is present in the mammalian brain and exhibits neuroprotective, and monoamine oxidase (MAO)-inhibiting properties. In the present study, in order to investigate the potential role of 1MeTIQ as an antidepressant, we tested antidepressant-like effects of 1MeTIQ in comparison with desipramine (a classic antidepressant) in the forced swimming test (FST), and using HPLC methodology, we measured the concentrations of monoamines (dopamine, noradrenaline, serotonin) and the rate of their metabolism. 1MeTIQ given alone as well as in combination with desipramine produced an antidepressant-like effect and decreased the immobility time in the FST. Neurochemical data have shown that 1MeTIQ like desipramine, activated the noradrenergic system. However, the mechanism of action of 1MeTIQ is broader than the actions of desipramine, and 1MeTIQ inhibits the MAO-dependent oxidation of dopamine and serotonin in all investigated structures. We can conclude that 1MeTIQ exhibits antidepressant-like activity in the FST in the rat. The mechanism of its antidepressant action differs from desipramine and seems to be mostly associated with the inhibition of the catabolism of monoamines and their increased concentrations in the brain. 1MeTIQ seems to be very beneficial from the clinical point of view as a reversible MAO inhibitor with a significant antidepressant effects.

Comparative behavioral and neurochemical studies of R- and S-1-methyl-1,2,3,4-tetrahydroisoquinoline stereoisomers in the rat

BACKGROUND 1-Methyl-1,2,3,4-tetrahydroisoquinoline (1-MeTIQ) is present in human and mammalian brain as a racemate (R,S) of two stereoisomers: R- and S-1MeTIQ. The racemate is a mixture of the endogenous, synthesized in the brain dextrorotary R-1MeTIQ, and the exogenous, levorotary form, S-1MeTIQ. METHODS In this study, we compared the effect of these two stereoisomers of 1MeTIQ with the racemate in the context of their influence on dopamine metabolism and in vivo dopamine release in the rat striatum. Additionally, a behavioral study was used to examine the influence of both enantiomers R- and S-1MeTIQ on locomotor activity of rats. RESULTS The behavioral studies showed that both R- and S-1MeTIQ enantiomers, like the racemate, produced biphasic effects: a slight decrease in the exploratory locomotor activity, and then an increase in the basal locomotor activity. Biochemical ex vivo experiments showed that S-1MeTIQ produced a much stronger inhibition of MAO-dependent dopamine oxidation than the racemate. R-1MeTIQ, in opposite to S-isoform and racemate, did not block dopamine oxidation in the structures which contain dopamine nerve endings (striatum, nucleus accumbens), and in fact did not suppress the level of its intraneuronal metabolite, DOPAC in these brain regions. However , an in vivo microdialysis study demonstrated that the racemate and both stereoisomers (R-1MeTIQ to a lesser extent) significantly elevated the concentration of dopamine in the extraneuronal space in the rat striatum. What is more, the concentration of an extraneuronal dopamine metabolite 3-methoxytyramine (3-MT), which is an indicator of its release, was considerably increased by all the compounds. CONCLUSIONS In summary of the results, it can be stated that S-1MeTIQ, like the racemate and in contrast to R-stereoisomer, inhibits MAO-dependent dopamine oxidation in all investigated brain structures. In addition, both these substances potentiated COMT-dependent O-methylation in the brain, however, also R-1MeTIQ produced such effect but to a lesser extent. In conclusion, we suggest that R- and S-1MeTIQ enantiomers like the racemate may demonstrate neuroprotective properties in the brain via the activation of dopamine O-methylation catabolic pathway and elevation of its methylated product - 3-MT.

The impact of 1MeTIQ on the dopaminergic system function in the 6-OHDA model of Parkinson's disease.

BACKGROUND Parkinsons disease (PD) is a progressive neurodegenerative disorder which is caused by degeneration of dopaminergic neurons of the nigrostriatal pathway. As a model of PD we used 6-hydroxydopamine (6-OHDA) which exerts toxic effects on catecholaminergic neurons and 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) as neuroprotective compound. The aim of the present study, was to investigate the potential neuroprotective properties of 1MeTIQ against 6-OHDA-induced neurotoxic effects in the rat. METHODS In the behavioral study, we measured locomotor activity and catalepsy. In the biochemical studies using HPLC methodology, we analyzed the concentration of dopamine and its metabolites in rat brain. RESULTS Behavioral tests showed that 6-OHDA decreased rat locomotor activity and produced an increase of catalepsy. These effects did not blocked by 1MeTIQ injections. Biochemical studies indicated that 6-OHDA lesion significantly reduced the concentration of dopamine and its metabolites in the nigro-striatal pathway in the lesioned (ipsilateral) side. Moreover, 6-OHDA induced an increase in the rate of dopamine oxidation. Both acute and chronic administration of 1MeTIQ did not reverse the effects of 6-OHDA lesion on the ipsilateral side, however, it produced a significant elevation of the dopamine concentration in the contralateral side. It is evident that multiple treatments with 1MeTIQ stimulate undamaged neurons to increased activity. CONCLUSION 1MeTIQ was shown to possess neuroprotective potential to the dopaminergic neurons damaged by 6-OHDA lesion. This compound has a protective effect but does not have neurorestorative capacity. It does not reverse damage already caused but will maintain the function and activity of undamaged dopamine neurons at physiological level.

Important role of 3-methoxytyramine in the inhibition of cocaine sensitization by 1-methyl-1,2,3,4-tetrahydroisoquinoline: an in vivo microdialysis study

1-Methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) is an endogenous compound with neuroprotective and antidopaminergic activities. Our previous research has shown that 1MeTIQ prevents morphine addiction and abates the expression of the reinstatement of cocaine self-administration. The current study investigated the mechanism of action of 1MeTIQ that is responsible for its considerable anticraving potential. Accordingly, we performed behavioral tests that measured the influence of 1MeTIQ on the locomotor activity of rats (Wistar) after a single cocaine (15 mg/kg, i.p.) dose and during cocaine sensitization (15 mg/kg, i.p.). In a neurochemical study, we examined the influence of 1MeTIQ on dopamine release in the rat striatum after a single cocaine administration and during cocaine sensitization using an in vivo microdialysis methodology. The data showed that 1MeTIQ (50 mg/kg, i.p.) only slightly inhibited cocaine-induced hyperactivity but completely antagonized the expression of locomotor cocaine sensitization. The in vivo microdialysis study demonstrated that the administration of 1MeTIQ before the acute cocaine injection intensified the cocaine-induced increase in dopamine release and produced a huge and long-lasting elevation of the extraneuronal concentration of dopamine (by approximately 1400%, p < 0.01) in the rat striatum. A significant increase in 3-methoxytyramine (3-MT) (by approximately 400%, p < 0.01) was also observed. During the expression of cocaine sensitization, the administration of 1MeTIQ before the reminder dose of cocaine produced an additional elevation of dopamine release but considerably more strongly increased the concentration of 3-MT in the synaptic cleft (by about 800%, p < 0.01). In light of these data and of our earlier in vitro and in vivo experiments showing a physiological role of 3-MT in the inhibitory regulation of excessive stimulation, we suggest that locomotor hyperactivity is dependent not only on dopamine concentration in the extracellular space, but also on the ratio of [DA/3-MT]. 1MeTIQ administered before the reminder dose of cocaine to cocaine-experienced rats plainly normalized the [DA/3-MT] ratio, which was increased by cocaine, and this effect may be responsible for its anti-addictive action. The results strongly support the view that 1MeTIQ may have a more general anti-abuse potential, and the extraneuronal metabolite of dopamine, 3-MT, may play a crucial role in its anti-craving effects.

Withdrawal from repeated administration of a low dose of reserpine induced opposing adaptive changes in the noradrenaline and serotonin system function: A behavioral and neurochemical ex vivo and in vivo studies in the rat

Reserpine is an inhibitor of the vesicular monoamine transporter 2 (VMAT2) and monoamine releaser, so it can be used as a pharmacological model of depression. In the present paper, we investigated the behavioral and neurochemical effects of withdrawal from acute and repeated administration of a low dose of reserpine (0.2 mg/kg) in Wistar Han rats. We demonstrated the behavioral and receptor oversensitivity (postsynaptic dopamine D1) during withdrawal from chronic reserpine. It was accompanied by a significant increase in motility in the locomotor activity test and climbing behavior in the forced swim test (FST). Neurochemical studies revealed that repeated but not acute administration the a low dose of reserpine triggered opposing adaptive changes in the noradrenergic and serotonin system function analyzed during reserpine withdrawal, i.e. 48 h after the last injection. The tissue concentration of noradrenaline was significantly decreased in the hypothalamus and nucleus accumbens only after repeated drug administration (by about 20% and 35% vs. control; p<0.05, respectively). On the other hand, the concentration of its extraneuronal metabolite, normetanephrine (NM) increased significantly in the VTA during withdrawal both from acute and chronic reserpine. The serotonin concentration was significantly reduced in the VTA after chronic reserpine (by about 40% vs. the control group, p<0.05) as well as its main metabolite, 5-HIAA (by about 30% vs. control; p<0.05) in the VTA and hypothalamus. Dopamine and its metabolites were not changed after acute or chronic reserpine administration. In vivo microdialysis studies clearly evidenced the lack of the effect of a single dose of reserpine, and its distinct effects after chronic treatment on the release of noradrenaline and serotonin in the rat striatum. In fact, the withdrawal from repeated administration of reserpine significantly increased an extraneuronal concentration of noradrenaline in the rat striatum but at the same time produced a distinct fall in the extraneuronal serotonin in this brain structure. On the basis of the presented behavioral and neurochemical experiments, we suggest that chronic administration of reserpine even in such low dose which not yet acted on the release of monoamines but produced an inhibition of VMAT2 caused a long-lasting disadvantageous effect of plasticity in the brain resembling depressive disorders.