What is the mechanism of toxicity of MPTP?
MPTP itself is not toxic, and as a lipophilic compound can cross the blood–brain barrier. Once inside the brain, MPTP is metabolized into the toxic cation 1-methyl-4-phenylpyridinium (MPP+) by the enzyme monoamine oxidase B (MAO-B) of glial cells, specifically astrocytes.
How does MPTP cross the blood brain barrier?
MPTP crosses the blood-brain barrier where it is taken up by astrocytes and converted to MPP+ by monamine oxidase-B (MAO-B). Subsequently, MPP+ is selectively taken up by dopaminergic neurons upon which it exerts intracellular neurotoxic effects.
What is MPTP model?
Among the most widely used models of Parkinson’s disease (PD) are those that employ toxins, especially 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Depending on the protocol used, MPTP yields large variations in nigral cell loss, striatal dopamine loss and behavioral deficits.
What cells does MPTP affect?
MPTP, which is lipid-soluble, readily penetrates the blood—brain barrier and enters the brain cells. Because it is amphiphilic, it is captured into acidic organelles, mostly lysosomes, of astrocytes. MPTP itself does not appear to be toxic, but its oxidized product, 1-methyl-4-phenylpyridinium (MPP+), is toxic.
What does Oxidopamine do to dopamine neurons?
The main use for oxidopamine in scientific research is to induce Parkinsonism in laboratory animals by lesioning the dopaminergic neurons of the substantia nigra pars compacta, in order to develop and test new medicines and treatments for Parkinson’s disease.
Where is the most likely site in the brain that MPTP exerts its toxic effects?
As a result, a rapid decrease in adenosine triphosphate (ATP) content occurs in the striatum and substantia nigra pars compacta (SNpc), the brain regions most sensitive to MPTP-induced neurotoxicity [17]. Interestingly, a significant ATP depletion can result from as little as 25% inhibition of complex I [18].
What are MPTP mice?
MPTP mouse models can be used to test the efficacy of many different types of drugs, including drugs that potentially neuroprotect the DAergic neurons in the midbrain. The mouse model is useful for studying mitochondrial dysfunction in Parkinsonism.
Where is MPTP found?
It occurs when an area of the brain, the substantia nigra, inexplicably dies. Patients are stiff, have trouble initiating movements and have tremors. The only thing known to cause Parkinson’s disease is a chemical, known as MPTP, discovered a decade ago as a contaminant in a botched batch of synthetic heroin.
What is Catecholaminergic system?
Catecholaminergic means “related to catecholamines”. The catecholamine neurotransmitters include dopamine, epinephrine (adrenaline), and norepinephrine (noradrenaline). A catecholaminergic agent (or drug) is a chemical which functions to directly modulate the catecholamine systems in the body or brain.
What enzyme converts dopa to dopamine?
aromatic amino acid decarboxylase
DOPA is converted to dopamine by aromatic amino acid decarboxylase. Dopamine-β-hydroxylase hydroxylates dopamine to norepinephrine, which is methylated to epinephrine by phenylethanolamine N-methyltransferase. Tyrosine hydroxylase is the rate-limiting enzyme of the pathway.
How was the MPTP model of Parkinson’s disease developed?
MPTP was first discovered by a chemistry student in 1976, who was trying to synthesize a synthetic heroin, but instead produced MPTP, which kills dopaminergic (DAergic) neurons [7]. Others, addicted to heroin, replicated this mistake in the early 1980s and developed severe PD-like symptoms.
What has MPTP?
Recently, a street-drug contaminant has appeared that can cause parkinsonism in drug abusers. The compound N-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) has been identified in underground laboratory preparations of a potent analog of meperidine (Demerol).
How does MPTP work in Parkinson’s disease cells?
After sys-temic administration of MPTP, its active metabolite, MPP +, accumulates within SNpc DA neurons, where it inhibits ATP production and stim-ulates superoxide radical for … MPTP causes damage to substantia nigra pars compacta (SNpc) dopaminergic (DA) neurons as seen in Parkinson’s disease (PD).
How is MPTP broken down into MPP +?
Figure 17.11. Effect of MPTP on dopaminergic neurons. MPTP is broken down by monoamine oxidase (MAO) into MPP +, which is taken up into dopaminergic nerve terminals by the dopamine transporter (DAT). Once inside, MPP + impairs mitochondrial function, killing the neuron.
Where does MPTP accumulate in the human body?
After sys-temic administration of MPTP, its active metabolite, MPP +, accumulates within SNpc DA neurons, where it inhibits ATP production and stim-ulates superoxide radical for … The parkinsonian toxin MPTP: action and mechanism
How is MPTP converted into an active toxin?
MPTP is converted into the active toxin 1-methyl-4-phenylpyridine (MPP+) by monoamine oxidase B (MAO-B) and is taken up by dopaminergic neurons, where it eventually causes neuronal necrosis or apoptosis. Massive neuronal loss is accompanied by loss of dopaminergic nerve terminals and dopaminergic neurotransmission,…