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Global Translational Medicine Parkinson’s: From cause to cure

group was most enriched in the ventral tier of the SNpc. non-motor symptoms in patients but also delay disease
The finding suggests that genetic risk factors for PD may progression. Over time, MAO-B inhibitors have evolved
selectively affect these susceptible neuron populations. 31 from non-selective, irreversible inhibitors to highly
In genetic forms of PD, genes such as SNCA, LRRK2, selective, reversible inhibitors.
and VPS35 are inherited in an autosomal dominant The first generation of MAO-B inhibitors had significant
manner, while PRKN, PINK1, DJ1, and other genes side effects, such as the “cheese effect,” which limited their
follow autosomal recessive inheritance. In addition, clinical application. The second generation, represented
variations in genes such as ATP13A2, DCTN1, DNAJC6, by selegiline and rasagiline, addressed selectivity issues to
FBXO7, PLA2G6, and SYNJ1 are associated with X-linked some extent but formed irreversible covalent bonds with
inheritance and atypical PD phenotypes. 30 the enzyme through an N-propylamine group. The third
Environmental factors such as occupational exposure generation, such as safinamide, features reversible and
and lifestyle also contribute to the occurrence and highly selective inhibitors, further improving safety and
36-38
progression of PD. efficacy.
3. Treatment for PD 3.2.3. Catechol-O-methyltransferase (COMT)
inhibitors
3.1. Pharmacological treatment
COMT is an enzyme responsible for the metabolism
Pharmacological treatment is essential for controlling of dopamine and other catechol compounds. COMT
symptoms, slowing disease progression, and improving inhibitors are recommended as first-line adjunctive therapy
the quality of life for PD patients. Advances in research to levodopa, effectively improving motor fluctuations in
on PD pathogenesis have driven the development of novel PD patients by increasing “on” time while reducing “off”
pharmacological therapies, offering new hope for patients. time.
Ongoing studies continue to expand the range of drug The main COMT inhibitors currently used in clinical
options, offering promising avenues for more effective practice include entacapone, tolcapone, and opicapone.
symptom management and disease modification.
Entacapone and opicapone are peripheral COMT
3.2. Conventional medication inhibitors, while tolcapone crosses the blood–brain barrier
and inhibits COMT activity within the brain. Opicapone,
3.2.1. Levodopa
a newer COMT inhibitor, overcomes some limitations of
Levodopa, a precursor of dopamine, is converted into earlier generations by offering sustained enzyme inhibition
dopamine in the central nervous system and plays an without the toxicity observed with previous agents. 39-41
irreplaceable role in the treatment of PD. The half-life of
levodopa in the blood is approximately 1 – 3 h, and its 3.2.4. Dopamine agonists
efficacy tends to decline with age and disease progression. Dopamine agonists stimulate dopamine receptors on the
32
In addition, long-term use of levodopa is associated with post-synaptic side of dopaminergic neurons, enhancing
side effects such as the wearing-off phenomenon, on-off the body’s response to dopamine stimulation. These drugs
phenomenon, and dyskinesia, which can significantly are effective in controlling both motor and certain non-
impact patients’ quality of life. To address these motor symptoms of PD.
33
challenges, the development of new levodopa formulations
aimed at extending its half-life and mitigating side effects Commonly used dopamine receptor agonists include
has become a research hotspot. New formulations, such non-ergoline agonists (such as pramipexole, ropinirole, and
as levodopa/carbidopa intestinal gel and sustained- rotigotine) and ergoline agonists (such as bromocriptine
release levodopa preparations, have successfully extended and cabergoline). Dopamine agonists can be used as
levodopa’s half-life in the bloodstream. Levodopa an initial treatment for early-stage PD or as adjunctive
34
42,43
inhalant (CVT-301) is rapidly absorbed through the lungs, treatment for advanced-stage PD.
reaching the brain within about 10 min, and provides rapid Studies suggest that, compared with levodopa, dopamine
relief of PD symptoms during off periods. 35 agonists may reduce the risk of motor complications
during the initial years of treatment. However, their long-
3.2.2. Monoamine oxidase-B inhibitors term effects and tolerability require further investigation.
Monoamine oxidase-B inhibitors (MAO-B) reduce Non-ergoline dopamine agonists show promise in treating
dopamine degradation by inhibiting monoamine oxidase both motor and non-motor symptoms, but side effects and
activity. MAO-B inhibitors not only alleviate motor and limited bioavailability restrict their broader application. 44

Volume 3 Issue 4 (2024) 5 doi: 10.36922/gtm.5082