Last updated on June 16, 2019 at 14:47
Mechanisms behind neurodegenerative diseases
Protein misfolding and aggregation is the first step in many neurodegenerative diseases, including Alzheimer and Parkinson disease, which are important in this topic. When proteins misfold their hydrophobic parts are exposed to the surface of the protein, which makes the proteins clump together into aggregates. These aggregates form structures we call amyloid deposits. We don’t know how, but these amyloid deposits cause neuronal death and therefore neurodegeneration.
Excitotoxicity: Despite being a physiological neurotransmitter glutamate is highly toxic to neurons. Glutamate activates multiple receptors on neurons, including NMDA, AMPA and metabotropic receptors. This allows Ca2+ to enter the cells, which activates many damaging processes, including production of reactive oxygen species, activation of proteases and lipases and increased production of arachidonic acid. It also causes the neuron to release more glutamate, which spreads this effect to other neurons as well.
Oxidative stress: The brain has high energy needs which are met almost entirely by oxidative phosphorylation. This process can produce reactive oxygen species as a by-product, especially during hypoxia. This increases the oxidative stress of the cell. Reactive oxygen species damage enzymes, membrane lipids and DNA.
Mitochondrial dysfunction is associated with aging, environmental toxins and genetic abnormalities. It may lead to oxidative stress and is a common feature of neurodegenerative diseases.
Drug treatment of Alzheimer disease
Alzheimer is characterised by loss of cholinergic neurons in the basal forebrain nuclei. The number of nicotinic receptors is also reduced. The mechanism of how Aβ amyloids damage these neurons selectively is not known.
Cholinesterase inhibitors (donepezil, rivastigmine and galantamine) and a drug called memantine are the only drugs used for treading Alzheimer disease. These drugs treat the symptoms of Alzheimer; no pharmacological treatment is available to slow the progression of the disease.
Donepezil, rivastigmine and galantamine are used in mild-moderate Alzheimer disease. They slightly improve cognitive functions.
Memantine is used in moderate-severe Alzheimer disease. It also slightly improves cognitive functions.
Mechanism of action:
Donepezil, rivastigmine and galantamine are acetylcholinesterase inhibitors. These drugs decrease the breakdown of acetylcholine at the synaptic cleft. Galantamine is also a positive allosteric modulator of nicotinic receptors, enhancing their action.
Memantine is an NMDA glutamate receptor antagonist. It decreases glutamate excitotoxicity.
Donepezil, rivastigmine, galantamine:
- Mild cholinergic side effects
- Abdominal pain
Drug treatment of Parkinson disease
Parkinson disease is characterised by loss of dopaminergic neurons in the basal ganglia, particularly in the substantia nigra. This causes disinhibition of cholinergic neurons in the striatum.
The treatment of Parkinson disease mostly involves increasing dopaminergic activity in the CNS. Pharmacological treatment improves symptoms but doesn’t slow the progression of the disease.
The important drugs here are levodopa, carbidopa, dopamine agonists (bromocriptine), MAO-B inhibitors (selegiline), COMT inhibitors (entacapone), safinamide, amantadine and anticholinergics like benztropine.
The first-line drug is levodopa, which is the most effective drug in treating Parkinson symptoms. However, its effectiveness in treating the symptoms diminishes after the patient has used the drug for 3 – 5 years. Because it’s only effective for a certain period of time, its use should be delayed as much as possible, by treating the disease with other drugs for as long as possible. Levodopa is always given with carbidopa or benserazide.
In younger patients dopamine agonists like bromocriptine are usually the first-line agents, while levodopa is “saved” until the disease progresses into worse stages.
MAO-B inhibitors like selegiline and COMT inhibitors like entacapone can be used to supplement levodopa therapy, to decrease the adverse effects associated with levodopa. Safinamide and amantadine can also be used as supplement therapy.
Anticholinergics inhibit the overactive cholinergic activity in the CNS. They are rarely used nowadays due to side effects.
Mechanism of action:
Levodopa is the same as the endogenous precursor to dopamine, L-DOPA. By supplying levodopa to the CNS the dopaminergic neurons have more substrate to convert into dopamine. Dopamine itself is not given because it doesn’t cross the blood-brain barrier, whereas levodopa does.
L-DOPA is converted to dopamine by DOPA decarboxylase in the body. To prevent levodopa from being converted to dopamine outside the CNS (which would cause side effects), levodopa is always given together with a decarboxylase inhibitor like carbidopa or benserazide. These decarboxylase inhibitors don’t cross the BBB, so they don’t impair dopamine synthesis in the CNS.
Dopamine agonists like bromocriptine bind to and activate postsynaptic dopamine D2 receptors.
COMT and MAO-B are enzymes that break down dopamine. Entacapone and selegiline inhibit these enzymes, increasing the level of dopamine in the CNS. Selegiline is also biotransformed into amphetamines, which stimulate dopamine release.
Safinamide acts by multiple mechanisms, including inhibiting MAO-B, inhibiting reuptake of DA and inhibiting ion channels.
Amantadine is an antiviral, but it also has NMDA antagonist and dopamine agonist effects.
These drugs should not be used in psychotic patients, as psychosis is often a result of too much dopaminergic transmission in the CNS.
Even with carbidopa more than 90% of levodopa is converted into dopamine in the periphery. Whether the effect comes from levodopa, COMT or MAO-B inhibitors or dopamine agonists, excess dopamine in the periphery and CNS causes side effects like:
- Peripheral dopamine
- Orthostatic hypotension
- Central dopamine
- Involuntary movements (dyskinesias)
Chronic use of levodopa is characterised by characteristic “on” and “off” episodes. During the “on” episodes the parkinsonism is relieved by the drug, but during the “off” episodes the parkinsonism returns until the “on” episode returns. COMT and MAO-B inhibitors can improve symptoms during the “off” episodes.
Drug treatment of Huntington disease
Huntington disease is characterised by decreased activity of glutamic acid decarboxylase, the enzyme responsible for GABA synthesis. It is believed that the loss of GABA-mediated inhibition of dopaminergic neurons in the basal ganglia is the underlying cause of Huntington.
Like for other neurodegenerative diseases pharmacological treatment can only treat symptoms and cannot slow progression of the disease. The aim of the treatment is to antagonize the effects of dopamine and enhance the effect of GABA.
The important drugs here are antipsychotics (haloperidol, clozapine), baclofen and tetrabenazine.
Mechanism of action:
Antipsychotics like haloperidol and clozapine are dopamine D2 antagonists.
Baclofen is a GABAB agonist.
Tetrabenazine is a VMAT inhibitor. VMAT is the protein that transports dopamine into transport vesicles. By inhibiting this protein transport vesicles will contain less dopamine, so dopaminergic transmission in the CNS decreases.
Drug treatment of stroke
During a stroke the necrotic brain tissue is surrounded by an area of ischaemic neurons, the penumbra, which are also at risk for necrosis. This drug treatment aims at saving as much of the penumbra as possible.
The only important drug here is alteplase.
Mechanism of action:
Alteplase is a recombinant tissue plasminogen activator, meaning that activates plasminogen. By converting plasminogen into plasmin, it breaks up any clots that would impair circulation to the penumbra.
Drug treatment of Wilson disease
Wilson disease is a genetic condition where copper accumulates in the body, especially in the brain and cornea.
It can be treated by molecules that chelate copper and form water-soluble complexes with it, that can be excreted by the body. The most commonly used drug is penicillamine.
Drug treatment of amyotrophic lateral sclerosis
ALS is characterised by degeneration of upper and lower motor neurons. Only one drug is used in the treatment of this disease, riluzole. Riluzole is a Na+ channel blocker that inhibits excitotoxicity.
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24. Drug abuse and dependence: general principles, opioids, anti-anxiety and hypnotic drugs, inhalants, ethanol