Page created on June 11, 2019. Last updated on April 3, 2022 at 15:45

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 disease 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.

Compounds

• Cholinesterase inhibitors
  • Donepezil
  • Rivastigmine
  • Galantamine
• Memantine

These drugs improve the symptoms of Alzheimer; no pharmacological treatment is available to slow the progression of the disease. However, these drugs also cause significant side effects in elderly. Non-pharmacological interventions are more important in case of AD.

Indications

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.

Side effects

The cholinesterase inhibitors have cholinergic side effects. These side effects are worse in elderly than in younger adults.

• Abdominal pain
• Nausea
• Diarrhoea
• Bradycardia, heart block

Memantine causes neuropsychiatric side effects like dizziness, confusion, and hallucinations.

(The story of aducanumab)

Aducanumab (Aduhelm®) is a drug which was recently (2021) approved by the FDA for the treatment of AD. As the only drug ever which aims to slow AD progression, the scientific and patient communities were excited. The monoclonal antibody binds to and removes amyloid plaques in patients with AD.

However, no studies have shown that there is a correlation between reduction of amyloid plaques and clinical improvement, and the results from the main studies of aducanumab were conflicting and did not show an overall effect at improving AD. It’s possible, and perhaps even likely, that the amyloid plaques are not causative of AD, but rather a consequence of the underlying pathophysiological process. Also, the drug significantly increases the risk of intracranial oedema or haemorrhage (>40% of patients taking the drug) and it’s expensive (28 000$ per year). The FDA’s scientific advisory committee, which advises the agency as to which drugs should be approved or not, voted 10 – 0 in favour of not approving the drug, citing questionable efficacy and safety, but the agency approved it anyway.

The FDA’s approval of the drug is the first time a drug has been approved without evidence of clinical improvement, and it may mark a paradigm shift in drug approval from clinical efficacy being mandatory for approval, to only theoretical evidence being enough for approval. This is very worrying. Drugs should only be approved when it’s known that they will work.

The EMA refused approval of the drug in december 2021, but the manufacturer has requested a re-evaluation as of april 2022. You can watch a short video on the topic here.

This is not important to know for the exam, but it’s something I think is important to be aware of.

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.

Compounds

• Dopamine substrates
  • Levodopa (L-DOPA)
• DOPA decarboxylase inhibitors
  • Carbidopa
  • Benserazide
• Dopamine agonists
  • Bromocriptine
  • Pramipexole
  • Cabergoline
• MAO-B inhibitors
  • Selegiline
  • Safinamide
• COMT inhibitors
  • Entacapone
• NMDA antagonists
  • Amantadine
• Anticholinergics
  • Benztropine
  • Biperiden

Indications

The first-line drug is levodopa, which is the most effective drug in treating Parkinson symptoms. However, its effectiveness in treating the symptoms diminishes as the disease progresses, and after a few years the patient usually requires other antiparkinson drugs as well. Levodopa is always given with carbidopa or benserazide. They’re administered multiple times a day to maintain dopamine availability throughout the day.

As the disease progresses, the patient experiences characteristic “on” and “off” episodes. During the “on” episodes the parkinsonism is relieved by levodopa, but during the “off” episodes the parkinsonism returns until the next dose is taken. More frequent dosing or addition of other antiparkinson drugs can improve symptoms during the “off” episodes or to supplement levodopa therapy.

A levodopa and carbidopa-containing gel can be administered directly into the intestines through a nasogastric tube or gastrostomy tube.

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 and decrease bioavailability in the CNS), levodopa is always given together with a decarboxylase inhibitor like carbidopa or benserazide. These decarboxylase inhibitors don’t cross the BBB, so they inhibit levodopa -> dopamine conversion in the periphery but not in the CNS.

Dopamine agonists bind to and activate postsynaptic dopamine D2 receptors directly.

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.

Contraindications

These drugs should not be used in psychotic patients, as psychosis is often a result of too much dopaminergic transmission in the CNS.

Side effects

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
  • Nausea
  • Arrhythmia
  • Orthostatic hypotension
• Central dopamine
  • Involuntary movements (dyskinesias)
  • Impulse control disorder
  • Confusion
  • Psychosis

Impulse control disorder is a special and interesting side effect of dopamine agonists. Patients may suddenly partake in uncontrolled behaviours like gambling, buying stuff they don’t need, wasting all their money, etc.

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. It’s characterised by chorea, personality disturbances, psychosis, and cognitive decline.

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.

Compounds

• Drugs for unintentional movements
  • Monoamine-depleting drugs
    • Tetrabenazine
  • Centrally acting muscle relaxants
    • Baclofen
  • NMDA antagonists
    • Amantadine
  • Benzodiazepines
• Drugs for psychosis
  • Atypical antipsychotics

Mechanism of action

Antipsychotics are dopamine D2 antagonists.

Baclofen is a GABA_B 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.

Amantadine is an NMDA antagonist.

Drug treatment of Wilson disease

• Penicillamine
• Trientine

Wilson disease is a genetic condition where copper accumulates in the body, especially in the brain and cornea. It usually affects adolescents and young adults.

It can be treated by molecules that chelate copper and form water-soluble complexes with it, that can be excreted by the body. The available copper chelators are penicillamine and trientine.

Drug treatment of amyotrophic lateral sclerosis

• Riluzole

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.

Drug treatment of ischaemic stroke

• Recombinant tissue plasminogen activator
  • Alteplase
• Antiplatelet
  • Aspirin

During an ischaemic 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.

Emergency thrombolysis with the use of a recombinant tissue plasminogen activator like alteplase may be performed. Aspirin is also used.

Mechanism of action

Alteplase is a recombinant tissue plasminogen activator. By converting plasminogen into plasmin it breaks up any clots that would impair circulation to the penumbra.