1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity in the rat: characterization and age-dependent effects

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a potent dopaminergic toxin that has been found to produce Parkinson's disease-like symptoms in humans and monkeys. The neurotoxic effects of MPTP appear to be reduced in rodents where multiple dosing procedures are required to demonstrate long-lasting neuronal deficits. In the present study, the neurotoxic effects of MPTP were further characterized in the rat. Following the repeated administration of MPTP, pronounced (60-80%) and dose-dependent depletions of striatal dopamine and serotonin concentrations were found in the rat brain. Time-course studies revealed that while striatal dopamine concentrations remained consistently reduced for at least 8 weeks following MPTP treatment, striatal serotonin depletions as well as MPTP-induced monoamine depletions in other brain regions were transient in nature. Pretreatment with the MAO-B inhibitor pargyline afforded a selective and complete protection of striatal dopamine levels without significantly affecting MPTP-induced striatal serotonin depletions. Similarly, treatment with ascorbic acid was found to selectively attenuate MPTP-induced dopamine depletions in rats. The neurotoxic effects of MPTP were also found to increase in the developing rat. No significant brain monoamine depletions were observed in neonatal rats following the repeated administration of MPTP. However, MPTP-induced neurotoxicity progressively increased in older rats. The present results indicate that when appropriate treatment procedures are used, a pronounced, selective, age-dependent, and long-lasting MPTP-induced reduction in striatal dopamine concentrations can be observed in the rat brain. The present results are discussed in reference to the putative mechanisms and species differences of MPTP-induced neurotoxicity.     

SKF-38393, a dopamine receptor agonist, attenuates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity

Parkinson's disease (PD) is characterized by progressive degeneration of nigrostriatal dopaminergic neurons. Several factors such as inhibition of the mitochondrial respiration, generation of hydroxyl radicals and reduced free radical defense mechanisms causing oxidative stress, have been postulated to contribute to the degeneration of dopaminergic neurons. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treated animals is a useful experimental model of PD, exhibiting most of the clinical features, as well as the main biochemical and pathologic symptoms of the disease. In the present study, we have examined a dopaminergic (D1) receptor agonist, SKF-38393 HCl (SKF) for its possible neuroprotective action against MPTP-induced insults on dopaminergic neurons. MPTP is converted by monoamine oxidase-B (MAO-B) to its neurotoxic metabolite 1-methyl-4-phenyl-pyridinium (MPP+), which is then taken up into the dopaminergic neurons. SKF-38393 had no effects either on total or monoamine oxidase B in the striatum. SKF-38393 blocked the MPTP-induced depletion of glutathione and attenuated MPTP-induced depletion of dopamine. Furthermore, it enhanced the activity of superoxide dismutase and hence mimicked the action of selegiline. The results of these studies are interpreted to suggest that SKF-38393 may prove a valuable drug in the treatment of Parkinson's disease.     

Levodopa-induced hyperactivity in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

The present study examines the motor responses of 10- to 12-month-old, male C57 mice that were either given intraperitoneal (IP) injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 30 mg/kg per day) or vehicle for 10 consecutive days, followed by IP injections of levodopa (200 mg/kg) plus carbidopa (25 mg/kg). Five days of MPTP exposure resulted in the Straub tail phenomenon and pronounced hypokinesia. However, during the next 5 days, motor activity returned to baseline, even with continued MPTP treatment. After 10 to 14 days of rest, all mice were then treated with levodopa/carbidopa twice daily for multiple, consecutive days. However, only the previously MPTP-treated animals became hyperkinetic, as compared to levodopa-treated control animals that were not previously exposed to MPTP. Abnormal activity included scratching, running, gnawing, and jumping movements. Hyperactivity lasted for approximately 2 hours after each levodopa injection and then returned to baseline, but the amount of hyperkinesia increased with additional days of levodopa treatment, even though the daily levodopa dose was not changed. These results demonstrate that levodopa can cause reproducible hyperactivity in mice that were previously exposed to MPTP.     

D-deprenyl protects nigrostriatal neurons against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurotoxicity

Selegiline (L-deprenyl) is believed to render protection against l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-neurotoxicity to a significant extent via a free radical scavenging mechanism, which is independent of its ability to inhibit monoamine oxidase-B (MAO-B) in the brain. We investigated the hydroxyl radical (.OH) scavenging action and neuroprotective effect of D-deprenyl, its less active isomer, in MPTP-induced dopaminergic neurotoxicity in mice to test whether the chemical structure of the molecule or its biological effects contribute to this property. To achieve this goal we studied the effects of D-deprenyl on: (1).OH production in a Fenton reaction; (2) MPTP-induced.OH generation and dopamine (DA) depletion in vivo, employing a sensitive HPLC-electrochemical procedure; and (3) formation of MPP(+) in vivo in the striatum following systemic administration of MPTP, employing an HPLC-photodiode array detection system. D-deprenyl inhibited ferrous citrate-induced.OH in vitro (0.45 microM) and MPTP-induced.OH in vivo in substantia nigra (SN) and in the striatum (1.0 mg/kg, i.p.). D-deprenyl did not, but L-deprenyl (0.5 mg/kg dose) did significantly inhibit formation of MPP(+) in the striatum 90 min following systemic MPTP injection. It failed to affect MAO-B activity at 0.5 mg/kg in the striatum, but effectively blocked MPTP-induced striatal DA depletion. The potency of D-deprenyl to scavenge MPTP-induced.OH in vivo and to render protection against the dopaminergic neurotoxicity without affecting dopamine turnover, MAO-B activity, or formation of MPP(+) in the brain indicates a direct involvement of.OH in the neurotoxic action of MPTP and antioxidant effect in the neuroprotective action of deprenyl.     

Protective effects of synthetic kynurenines on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in mice

Mitochondrial complex I inhibition is thought to underlie the neurodegenerative process in Parkinson's disease (PD). Moreover, an overproduction of nitric oxide due to both cytosolic (iNOS) and mitochondrial (i-mtNOS) inducible nitric oxide synthases causes free radicals generation and oxidative/nitrosative stress, contributing to mitochondrial dysfunction and neuronal cell death. Looking for active molecules against mitochondrial dysfunction and inflammatory response in PD, we show here the effects of four synthetic kynurenines in the MPTP model of PD in mice. After MPTP administration, mitochondria from substantia nigra and, in a lesser extent, from striatum showed a significant increase in i-mtNOS activity, nitric oxide production, oxidative stress, and complex I inhibition. The four kynurenines assayed counteracted the effects of MPTP, reducing iNOS/i-mtNOS activity, and restoring the activity of the complex I. Consequently, the cytosolic and mitochondrial oxidative/nitrosative stress returned to control values. The results suggest that the kynurenines here reported represent a family of synthetic compounds with neuroprotective properties against PD, and that they can serve as templates for the design of new drugs able to target the mitochondria.     

Korean red ginseng suppresses 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced inflammation in the substantia nigra and colon

Parkinson’s disease (PD) is a neurodegenerative disease involving dopaminergic neuronal death in the substantia nigra (SN); recent studies have shown that interactions between gut and brain play a critical role in the pathogenesis of PD. In this study, the anti-inflammatory effect of Korean red ginseng (KRG) and the changes in gut microbiota were evaluated in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model. Male nine-week-old C57BL/6 mice were injected intraperitoneally with 30 mg/kg of MPTP at 24-h intervals for 5 days. Two hours after the daily MPTP injection, the mice were orally administered 100 mg/kg of KRG, which continued for 7 days beyond the MPTP injections, for a total of 12 consecutive days. Eight days after the final KRG administration, the pole and rotarod tests were performed and brain and colon samples of the mice were collected. Dopaminergic neuronal death, activation of microglia and astrocytes, α-synuclein and expressions of inflammatory cytokines and disruption of tight junction were evaluated. In addition, 16S ribosomal RNA gene sequencing of mouse fecal samples was performed to investigate microbiome changes. KRG treatment prevented MPTP-induced behavioral impairment, dopaminergic neuronal death, activation of microglia and astrocytes in the nigrostriatal pathway, disruption of tight junction and the increase in α-synuclein, interleukin-1β and tumor necrosis factor-α expression in the colon. The 16S rRNA sequencing revealed that MPTP altered the number of bacterial species and their relative abundances, which were partially suppressed by KRG treatment. Especially, KRG suppressed the abundance of the inflammation-related phylum Verrucomicrobia and genera Ruminococcus and Akkermansia (especially Akkermansia muciniphila), and elevated the abundance of Eubacterium, which produces the anti-inflammatory substances. These findings suggest that KRG prevents MPTP-induced dopaminergic neuronal death, activation of microglia and astrocytes, and accumulation of α-synuclein in the SN, and the regulation of inflammation-related factors in the colon may influence the effect.     

Adaptive acetylcholinesterase splicing patterns attenuate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinsonism in mice

Balanced dopaminergic cholinergic interactions are crucial for proper basal ganglia function. This is dramatically demonstrated by the worsening of Parkinson's disease symptoms following acetylcholinesterase (AChE) inhibition. Typically, in the brain, the synapse-anchored synaptic AChE (AChE-S) variant is prevalent whereas the soluble readthrough AChE (AChE-R) variant is induced in response to cholinesterase inhibition or stress. Because of the known functional differences between these variants and the fact that AChE-R expression is triggered by various stimuli that themselves are often associated with Parkinson's disease risk, we hypothesized that the splice shift to AChE-R plays a functional role in Parkinsonian progression. After establishing that Paraoxon-induced AChE inhibition indeed aggravates experimental Parkinsonism triggered by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice, we tested the roles of individual AChE variants by exposing transgenic mice overexpressing either the AChE-S or AChE-R variant to MPTP. Differential reductions of tyrosine hydroxylase levels in the striatum and substantia nigra indicated that transgenic AChE-R expression confers resistance as compared with the parent FVB/N strain. In contrast, AChE-S overexpression accelerated the MPTP-induced damage. Survival, behavioral measures and plasma corticosterone levels were also compatible with the extent of the dopaminergic damage. Our findings highlight the functional differences between individual AChE variants and indicate that a naturally occurring stress or AChE inhibitor-induced splicing shift can act to minimize dopaminergic cholinergic imbalances. We propose that inherited or acquired alternative splicing deficits could accelerate Parkinsonism and that, correspondingly, adaptive alternative splicing events may attenuate disease progression.     

Cigarette smoke and nicotine protect dopaminergic neurons against the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Parkinsonian toxin

Epidemiological studies have found a negative association between cigarette smoking and Parkinson's disease (PD). In order to analyze the putative neuroprotective effect of cigarette smoke and nicotine, one of its major constituents, we examined their effects in an animal model of PD provoked by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication. Two groups of mice were chronically exposed to cigarette smoke (a low exposure subgroup and a high exposure subgroup; 5 exposures per day at 2-h intervals), two other groups received nicotine treatment (two doses tested 0.2 and 2 mg/kg, 5 injections i.p. per day at 2-h intervals) and one group placebo. On day 8 after the beginning of the treatment, 4 injections of MPTP hydrochloride (15 mg/kg, i.p., at 2-h intervals) or saline were administered to these animals. Nicotine and cotinine plasmatic concentration was quantified by the HPLC method, and degeneration of the nigrostriatal system was assessed by tyrosine hydroxylase (TH) immunohistochemistry. The loss of dopaminergic neurons induced by MPTP in the substantia nigra was significantly less severe in the chronic nicotine treatment groups (at 0.2 and 2 mg/kg) and the low exposure to cigarette smoke group than in the high exposure to cigarette smoke subgroup and the placebo treated subgroup. In contrast, no preservation of TH immunostaining of nerve terminals was observed in the striatum in any group. This suggests that nicotine and low exposure to cigarette smoke may have a neuroprotective effect on the dopaminergic nigrostriatal system by an as yet unknown mechanism.     

Dopamine differentiation factors increase striatal dopaminergic function in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mice

We have previously shown that muscle-derived differentiation factors (MDF) and human recombinant acidic fibroblast growth factor (aFGF) have beneficial behavioral and neurochemical effects on the nigrostriatal dopaminergic neurons of 6-hydroxy-dopamine (6-OHDA)-lesioned rats (Jin and Iacovitti: Neurobiol Dis 2:1–12, 1995). In the present study, we determined the effects of similar treatments on mice treated with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Five days after unilateral striatal infusion of MDF or aFGF into MPTP-lesioned mice, striatal tyrosine hydroxylase (TH) activity and dihydroxyphenylacetic acid (DOPAC) levels were bilaterally increased (20–35%) compared to untreated (lesion only) or control (phosphate buffered saline + bovine serum albumin) mice. These increases, however, were not accompanied by change in dopamine (DA) levels, indicating an elevation of DA synthesis (TH/DA) and turnover (DOPAC/DA). The present findings that MDF and aFGF may have neurochemical effects in vivo on the lesioned nigrostriatal dopaminergic system suggest their potential pharmacological role in the treatment of Parkinson's disease. © 1996 Wiley-Liss, Inc.     

Profiling changes in gait dynamics resulting from progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced nigrostriatal lesioning

Current behavioral measurements for motor impairment are not consistently sensitive in rodent models of partial nigrostriatal dopamine (DA) depletion. In addition to exploratory and somatosensory behavior, motor skills that are thought to be directly translatable to human Parkinson's disease patients are assessed. However, many of these motor tests require the training and learning of particular tasks, so it cannot be determined whether impairments are due to motor or to learning deficit. Therefore, we have quantified multiple temporal and spatial indices of gait dynamics in a model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced partial nigrostriatal lesioning using a treadmill apparatus requiring no prior training. Three days following the cessation of progressively increased MPTP administration, rearing and foot-fault behaviors showed significant deficit. Ten days after the final MPTP injection, gait dynamics were assessed and indicated differences between MPTP- and vehicle-treated animals. The major significant changes were in stride length, frequency, duration, and number of steps. Three weeks following a progressively increased dose of MPTP (administered 5 days per week over the course of 4 weeks), mice showed a 63% decrease in tyrosine hydroxylase-immunoreactive (TH-ir) nigrostriatal neurons in the substantia nigra pars compacta and a 72% decrease in TH-ir terminals in the caudate-putamen. This suggests that there is a continued effect of progressively increased MPTP on nigrostriatal DA neurons, correlated with rearing and foot-fault behaviors and further characterized by differences in temporal and spatial measurements of gait dynamics.     

Dextromethorphan prevents the diethyldithiocarbamate enhancement of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity in mice

In this report we show that dextromethorphan, a non-opioid cough suppressant, prevents the neurodegeneration of dopaminergic neurons in the substantia nigra of mice treated with diethyldithiocarbamate (DDC) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). This effect is further substantiated by the assessment of dopamine (DA) content in the striatum of these animals. Dextromethorphan does not attenuate the striatal DA fall induced by MPTP alone but completely prevents DDC-induced enhancement after the combined treatment. Moreover, a study of DA metabolites has confirmed this neuroprotective property. The striatal levels of serotonin, which were studied as a control neuronal marker, did not change with any of the treatments administered. Furthermore, we show that dextromethorphan reduces the toxicity of glutamate against dopamine neurons in mesencephalic cell cultures. In line with previous data suggesting that dextromethorphan can prevent neuronal damage, our observations supply new evidence regarding the possibility of this compound being of therapeutic use in neurodegenerative diseases.     

Anti-parkinsonian effects of octacosanol in 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine-treated mice

Our previous research showed that octacosanol exerted its protective effects in 6-hydroxydopamine-induced Parkinsonian rats. The goal of this study was to investigate whether octacosanol would attenuate neurotoxicity in 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-treated C57BL/6N mice and its potential mechanism. Behavioral tests, tyrosine hydroxylase immunohistochemistry and western blot were used to investigate the effects of octacosanol in a mouse model of Parkinson’s disease. Oral administration of octacosanol (100 mg/kg) significantly improved behavioral impairments in mice treated by MPTP and markedly ameliorated morphological appearances of tyrosine hydroxylase-positive neuronal cells in the substantia nigra. Furthermore, octacosanol blocked MPTP-induced phosphorylation of p38MAPK and JNK, but not ERK1/2. These findings implicated that the protective effects afforded by octacosanol might be mediated by blocking the phosphorylation of p38MAPK and JNK on the signal transduction in vivo. Considering its excellent tolerability, octacosanol might be considered as a candidate agent for clinical application in treating Parkinson’s disease.     

7-Nitroindazole prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced ATP loss in the mouse striatum

The neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is dependent upon the MAO-B (monoamine oxidase type B)-catalyzed production of 1-methyl-4-phenylpyridinium ion (MPP(+)) and is likely to involve a perturbation of energy metabolism. Protection against MPTP neurotoxicity has been shown by treating mice with 7-nitroindazole (7-NI), a reversible inhibitor of both MAO-B and neuronal nitric oxide synthase (nNOS) activity. The objective of the present study was to evaluate (i) the relationship between the neuroprotective effect of 7-NI and MPTP-induced energy deficiency, and (ii) the role of nitric oxide production as a potential mechanism for energy perturbation after MPTP exposure. Maximum protection against striatal dopamine depletion and nigral neuronal loss was achieved when 7-NI (50 mg/kg, i.p.) was administered to C57BL/6 mice immediately before and after MPTP (50 mg/kg, s.c.). This short-term regimen of 7-NI administration parallels the time when MPTP exposure causes energy failure. 7-NI also completely prevented the loss of striatal ATP that occurs in mice during the initial hours after MPTP administration. In contrast, N(G)-nitro-L-arginine (two injections of 50 mg/kg each, given i.p. 20 and 4 h prior to MPTP), another NOS inhibitor, failed to affect MPTP-induced ATP depletion. Taken together, data indicate that (i) a temporal and causal relationship exists between the neuroprotective effect of 7-NI and its ability to counteract ATP reduction, and (ii) MAO-B rather than NOS inhibition is the mechanism by which 7-NI counteracts MPTP-induced ATP depletion.     

Role of extracellular-regulated kinase and c-Jun NH2-terminal kinase in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurofilament phosphorylation

The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes selective degeneration of dopaminergic neurons in which the c-Jun NH2-terminal kinase (JNK) signalling cascade has been implicated. We have employed a differentiated mouse neuroblastoma N2a cell model to investigate the involvement of JNK and extracellular-regulated kinase (ERK) in MPTP-mediated toxicity and their role in neurofilament heavy chain (NF-H) phosphorylation. Acute treatment with a cytotoxic MPTP concentration (5 mM) caused rapid and sustained JNK phosphorylation and ERK dephosphorylation, accompanied by cell death. In contrast, subcytotoxic concentrations of 10 microM MPTP resulted in lower, transient JNK activation in the presence of sustained ERK activity. This resulted in an aberrant increase in a phosphorylation-dependent NF-H epitope, perikaryal accumulation of NF-H, and loss of axon-like processes, prior to cell death. Inhibition of MEK kinase, using PD98059, showed that MEK 1/2 or the downstream kinase, ERK, is required for N2a cell differentiation, NF-H phosphorylation and survival. Indeed, MPTP-induced cell death was exacerbated by the presence of PD98059. However, in the presence of MPTP, reducing JNK activity by using an upstream specific mixed-lineage kinase inhibitor (CEP-11004) significantly attenuated aberrant NF-H phosphorylation and perikaryal NF-H accumulation and maintained axon-like processes, in addition to attenuating cell death. This study reports a switch in the predominant kinase involved in NF phosphorylation in a neuronal cell model and may have implications for the formation of inclusions. Our studies provide further evidence that modulation of the JNK pathway could have a role in alleviating neuronal cell death.     

Aging and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced degeneration of dopaminergic neurons in the substantia nigra

This study assessed the influence of aging on substantia nigra degeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Extensive neuronal degeneration was found in the substantia nigra of older (8–12 months of age) but not younger (6–8 weeks of age) mice given MPTP. Older mice did not have higher brain concentrations of either MPTP or 1-methyl-4-phenylpyridinium (MPP⁺), the putative toxic metabolite of MPTP, to account for the greater toxicity. In fact, older mice metabolized MPTP more rapidly than younger mice, probably because of the increase in monoamine oxidase activity that occurs with aging. Striatal synaptosomes from older mice did not accumulate more [³H]MPP⁺ than synaptosomes from younger mice. Thus, it is concluded that the greater neurodegenerative effect of MPTP in older animals is not due to greater levels or uptake of MPP⁺, but rather is related to a true increase in sensitivity of older dopaminergic cells to MPTP. For comparative purposes, the toxic effect of another dopaminergic neurotoxin, methamphetamine, was tested. Older animals were not more sensitive than young mature animals to the toxic effect of methamphetamine. This finding indicates that the increased sensitivity of older dopaminergic neurons to MPTP is selective. The link established here between aging and the neurodegenerative effect of MPTP, a toxin which produces parkinsonism in humans, provides a mechanism by which an age-related neurodegenerative disorder such as Parkinson's disease could be caused by an MPTP-like toxin in the environment.     

The dopamine-depleting effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in CD-1 mice are gender-dependent

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a selective dopaminergic neurotoxin affecting the nigrostriatal system in a variety of species including, rodents, nonhuman primates and humans. There exists, however, a great deal of variability in the sensitivity of different species to the effects of MPTP. The present study was designed to determine whether a significant difference in gender susceptibility to the toxin in CD-1 mice might also exist. A dosing regiment of 30 mg/kg MPTP once a day for 3 days (90 mg/kg total dose) in 4-month-old male and female CD-1 mice led to a significant depletion of striatal dopamine in both sexes. Two way ANOVA analysis of a time-course generated by measuring striatal dopamine at 4, 12 and 24 h after each dose of MPTP revealed that the initial dopamine reduction is significantly greater in male CD-1 mice (P < 0.001). Further, dopamine levels were reduced to a greater extent in male mice 5 days after the last dose (31 % vs. 59% of control; P < 0.02). HPLC analysis using fluorescence detection revealed no difference in the striatal nor the cerebellar levels of MPP+ between the two sexes, however, accumulation of larger amounts of MPP⁺ was observed in the livers of the female mice. These findings suggest that, while female CD-1 mice are more resistant to the dopamine-depleting effects of MPTP, this gender difference is not due to decreased production or accumulation of striatal MPP⁺.     

Neuroprotective potential of Quercetin in combination with piperine against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity

1-Methy-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)is a neurotoxin that selectively damages dopaminergic neurons in the substantia nigra pars compacta and induces Parkinson’s like symptoms in rodents.Quercetin(QC)is a natural polyphenolic bioflavonoid with potent antioxidant and anti-inflammatory properties but lacks of clinical attraction due to low oral bioavailability.Piperine is a well established bioavailability enhancer used pre-clinically to improve the bioavailability of antioxidants(e.g.,Quercetin).Therefore,the present study was designed to evaluate the neuroprotective potential of QC together with piperine against MPTP-induced neurotoxicity in rats.MPTP(100μg/μL/rat,bilaterally)was injected intranigrally on days 1,4 and 7 using a digital stereotaxic apparatus.QC(25 and 50 mg/kg,intragastrically)and QC(25 mg/kg,intragastrically)in combination with piperine(2.5 mg/kg,intragastrically)were administered daily for 14 days starting from day 8 after the 3~(rd) injection of MPTP.On day 22,animals were sacrificed and the striatum was isolated for oxidative stress parameter(thiobarbituric acid reactive substances,nitrite and glutathione),neuroinflammatory cytokine(interleukin-1β,interleukin-6,and tumor necrosis factor-α)and neurotransmitter(dopamine,norepinephrine,serotonin,gamma-aminobutyric acid,glutamate,3,4-dihydroxyphenylacetic acid,homovanillic acid,and 5-hydroxyindoleacetic acid)evaluations.Bilateral infusion of MPTP into substantia nigra pars compacta led to significant motor deficits as evidenced by impairments in locomotor activity and rotarod performance in open field test and grip strength and narrow beam walk performance.Both QC(25 and 50 mg/kg)and QC(25 mg/kg)in combination with piperine(2.5 mg/kg),in particular the combination therapy,significantly improved MPTP-induced behavioral abnormalities in rats,reversed the abnormal alterations of neurotransmitters in the striatum,and alleviated oxidative stress and inflammatory response in the striatum.These findings indicate that piperine can enhance the antioxidant and anti-inflammatory properties of QC,and QC in combination with piperine exhibits strong neuroprotective effects against MPTP-induced neurotoxicity.     

Enhanced tumor growth in brain dopamine-depleted mice following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment

Brain dopamine influences immune functions and the role of immune functions in tumor growth is well established. Therefore, a study has been carried out to evaluate the correlation, if any, between brain dopamine and tumor growth. MPTP selectively destroys dopaminergic neurons in the brain. In the present study, Ehrlich carcinoma growth was evaluated in MPTP-treated mice. Results showed a correlation between depletion of striatal dopamine and enhanced tumor growth. Since in the present study striatal dopamine depletion in mice was associated with significantly decreased immune responses, the suggested correlation between brain dopamine and tumor growth was possibly mediated by the immune system.