Effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on retinal dopaminergic system in mice

Hamilton, W. Ryan; Trickler, William J.; Robinson, Bonnie; Paule, Merle G.; Ali, Syed F.

doi:10.1016/j.neulet.2012.02.085

Cited by 9 publications

(10 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These results are in good agreement with the published data stating that the dopamine level decreases in the retina of mice with MPTP-induced parkinsonism [24]. It is interesting that no changes in the plasma level of norepinephrine as compared to the control were detected in the mouse models of both PD stages, unlike the situation with the norepinephrine level in the eyes [25].…”

Section: Discussionsupporting

confidence: 91%

Biochemical and Functional Changes in the Eye As a Manifestation of Systemic Degeneration of the Nervous System in Parkinsonism

Kim¹,

Павленко²,

Катаргина³

et al. 2018

Acta Naturae

View full text Add to dashboard Cite

Parkinson’s disease (PD) is a systemic neurodegenerative condition caused by the death of dopaminergic neurons of the nigrostriatal system of the brain. This disease is diagnosed after most neurons have already been lost, which explains the low efficiency of treatment. Hope for increasing treatment efficiency rests in the development of new strategies for early diagnosis of PD based on a search for peripheral markers that appear as early changes in non-motor functions. Since impairment of the visual function is one of the manifestations of PD, the purpose of our work was to identify biochemical and physiological changes in a mouse’s eye and eyelid in models of preclinical (presymptomatic) and clinical (symptomatic) stages of PD. We found that the norepinephrine, dopamine, and serotonin levels in the mouse eye reduced not only in the model of the early clinical stage, but also in the model of preclinical stage, an indication that pathological changes in the monoaminergic systems of the brain had affected the eye even before the motor disorders emerged. Moreover, in both models of PD, mice had increased intraocular pressure, indicating the development of both metabolic and functional impairments, which can be used as diagnostic markers. Unlike in the eye, the serotonin level in the eyelid was increased in mice at both parkinsonism stages and in presymptomatic mice to a much higher extent than in symptomatic ones. Given that serotonin is involved in the regulation of lacrimal glands of the eyelid, an increase in its level in parkinsonian mice should alter the composition of tear fluid, which could serve as a diagnostic marker of early stage of PD. Thus, the changes in the metabolism of monoamines in the eye and eyelid observed in mice at the early stage of parkinsonism are accompanied by changes in the function of these structures and, therefore, can be used as diagnostic markers of the early stage of PD.

show abstract

Section: Discussionsupporting

confidence: 91%

Biochemical and Functional Changes in the Eye As a Manifestation of Systemic Degeneration of the Nervous System in Parkinsonism

Kim¹,

Павленко²,

Катаргина³

et al. 2018

Acta Naturae

View full text Add to dashboard Cite

show abstract

“…In the literature, the lowest single doses of MPTP found to be given to C57BL/6J mice was 6.25–12.5 mg/kg, the lower of which resulted in significant striatal dopamine loss, but no effect on TH levels [21]. Low (2×5 mg/kg) and high (3×10 mg/kg) doses of MPTP were reported to have differential effects on retinal DA, DOPAC and HVA levels, with low dose effects on DOPAC levels not observed at the higher dose, which was hypothesized to be the result of inhibition of MAO at low MPTP doses [30]. With regard to loss of DA with low dose MPTP, there are multiple potential mechanisms that may contribute to this loss that occurs without corresponding dopamine neuron loss.…”

Section: Discussionmentioning

confidence: 99%

Single low doses of MPTP decrease tyrosine hydroxylase expression in the absence of overt neuron loss

et al. 2017

View full text Add to dashboard Cite

Parkinson’s disease (PD) is the second most common age-related neurodegenerative disease. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a prototypical neurotoxicant used in mice to mimic primary features of PD pathology including striatal dopamine depletion and dopamine neuron loss in the substantia nigra pars compacta (SNc). In the literature, there are several experimental paradigms involving multiple doses of MPTP that are used to elicit dopamine neuron loss. However, a recent study reported that a single low dose caused significant loss of dopamine neurons. Here, we determined the effect of a single intraperitoneal injection of one of three doses of MPTP (0.1, 2 and 20 mg/kg) on dopamine neurons, labeled by tyrosine hydroxylase (TH+), and total neuron number (Nissl+) in the SNc using unbiased stereological counting. Data reveal a significant loss of neurons in the SNc (TH+ and Nissl+−) only in the group treated with 20 mg/kg MPTP. Groups treated with lower dose of MPTP (0.1 and 2 mg/kg) only showed significant loss of TH+ neurons rather than TH+ and Nissl+. Striatal dopamine levels were decreased in the groups treated with 2 and 20 mg/kg MPTP and striatal terminal markers including, TH and the dopamine transporter (DAT), were only decreased in the groups treated with 20 mg/kg MPTP. These data demonstrate that lower doses of MPTP likely result in loss of TH expression rather than actual dopamine neuron loss in the SN. This finding reinforces the need to measure both total neuron number along with TH+ cells in determining dopamine neuron loss.

show abstract

“…A 25 µl aliquot from each sample was directly injected into an HPLC/EC system connected to BASi liquid chromatography pump (West Lafayette, IN, USA), a Supelco Supelcoil LC-18 (7.5 cm × 4.6 mm) analytical column, an amperometric detector and an LC-17 oxidative flow cell (BASi) with a glassy carbon electrode versus an Ag–AgCl reference electrode which was maintained at a potential of 0.75 V. The HPLC mobile phase consisted of potassium phosphate pH 3.0, methanol and heptane-sulfonic acid (Ali et al, 1993) and chromatograms were recorded and integrated using a BASi HPLC system with Epsilon Integrator. Concentrations of DA, DOPAC and HVA were calculated against a series of internally prepared, known standards and ratios of DOPAC/DA and HVA/DA were calculated as estimates of DA release and turnover (Boireau et al, 1990; Hamilton et al, 2012). …”

Section: Methodsmentioning

confidence: 99%

Distinct effects of ketamine and acetyl l-carnitine on the dopamine system in zebrafish

Robinson

Dumas

Cuevas

et al. 2016

Neurotoxicology and Teratology

Self Cite

View full text Add to dashboard Cite

Ketamine, a noncompetitive N-methyl-d-aspartic acid (NMDA) receptor antagonist is commonly used as a pediatric anesthetic. We have previously shown that acetyl L-carnitine (ALCAR) prevents ketamine toxicity in zebrafish embryos. In mammals, ketamine is known to modulate the dopaminergic system. NMDA receptor antagonists are considered as promising anti-depressants, but the exact mechanism of their function is unclear. Here, we measured the levels of dopamine (DA) and its metabolites, 3, 4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the zebrafish embryos exposed to ketamine in the presence and absence of 0.5 mM ALCAR. Ketamine, at lower doses (0.1–0.3 mM), did not produce significant changes in DA, DOPAC or HVA levels in 52 h post-fertilization embryos treated for 24 h. In these embryos, tyrosine hydroxylase (TH) mRNA expression remained unchanged. However, 2 mM ketamine (internal embryo exposure levels equivalent to human anesthetic plasma concentration) significantly reduced DA level and TH mRNA indicating that DA synthesis was adversely affected. In the presence or absence of 2 mM ketamine, ALCAR showed similar effects on DA level and TH mRNA, but increased DOPAC level compared to control. ALCAR reversed 2 mM ketamine-induced reduction in HVA levels. With ALCAR alone, the expression of genes encoding the DA metabolizing enzymes, MAO (monoamine oxidase) and catechol-O-methyltransferase (COMT), was not affected. However, ketamine altered MAO mRNA expression, except at the 0.1 mM dose. COMT transcripts were reduced in the 2 mM ketamine-treated group. These distinct effects of ketamine and ALCAR on the DA system may shed some light on the mechanism on how ketamine can work as an anti-depressant, especially at sub-anesthetic doses that do not affect DA metabolism and suppress MAO gene expression.

show abstract

Effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on retinal dopaminergic system in mice

Cited by 9 publications

References 35 publications

Biochemical and Functional Changes in the Eye As a Manifestation of Systemic Degeneration of the Nervous System in Parkinsonism

Biochemical and Functional Changes in the Eye As a Manifestation of Systemic Degeneration of the Nervous System in Parkinsonism

Single low doses of MPTP decrease tyrosine hydroxylase expression in the absence of overt neuron loss

Distinct effects of ketamine and acetyl l-carnitine on the dopamine system in zebrafish

Contact Info

Product

Resources

About