1,1 Dopamine precursor supplements
Levodopa analogues are the dopamine precursor supplements commonly used in clinical practice, and are the most common and effective method to supplement dopamine in the brain. Application of dopamine precursors levodopa can enter the brain through the blood-brain barrier and be decarboxylated by dopa decarboxylase into dopamine, thus replenishing dopamine in the brain. It is inactive by itself and is decarboxylated into dopamine (DA) by the action of amino acid decarboxylase after entering the brain.
Levodopa drugs have therapeutic effects by replenishing DA in the body, improving muscle tonus and dyskinesia, and are more effective in myotonia and bradykinesia than in tremor; they are effective in younger patients and in mildly ill patients, but can lead to motor complications after long-term, high-dose use. Some studies in vitro suggest that levodopa may have toxic effects, but they remain controversial. The incidence of motor complications is about 10,0% per year in diagnosed patients over 60 years of age, but younger-onset patients develop motor complications more rapidly, with 70,0% developing motor complications 3 years after diagnosis. However, levodopa remains the most commonly used medication for PD and is effective in improving motor bradykinesia and rigidity. In practice, levodopa can be used as the gold standard by which other drugs are judged.
1,2 Anticholinergic drugs
These drugs have the ability to inhibit the activity of acetylcholine and accordingly increase the effect of dopamine in the brain and adjust the transmitter balance in the striatum. It is suitable for the treatment of early mild disease patients and as an adjuvant to levodopa. A decrease in the activity of dopamine in the central nervous system can lead to an increase in cholinergic effects. Prior to the use of levodopa, anticholinergic drugs were the only drugs used to treat PD and are still particularly indicated for PD patients with tremor and salivation. The main drugs in this class are benzhexol (Antan), which is indicated for patients with mild symptoms and early onset of tremor. The use of these drugs is limited especially in the elderly because they inhibit acetylcholine in the central nervous system, resulting in diminished cognitive function. Recent studies have found that this class of drugs may cause impaired cognitive function by damaging the medial temporal lobe, including the hippocampus.
1,3 Pro-dopamine-releasing agents
Amantadine is a representative of this class of drugs. It can enhance the function of DA in various ways, can enhance presynaptic synthesis and release of dopamine, reduce the reabsorption of dopamine, and has a strong effect on the relief of muscle tonicity, tremor and dyskinesia in PD patients, which is better than anticholinergic drugs, but weaker than levodopa drugs. It also has anticholinergic effects. It can be combined with anticholinergic drugs or levodopa. Side effects include nausea, insomnia, headache, confusion, etc. It is contraindicated in patients with epilepsy.
1.4 Dopamine receptor agonists (DARA)
These drugs act directly on the dopamine receptors on the striatum to play a therapeutic role, and the agonists alone can effectively control dopaminergic symptoms in a short period of time, but inevitably have to be combined with levodopa throughout the course of the disease, or can be combined with levodopa or applied when levodopa fails. DA receptor agonists, because of their similar molecular conformation to DA, can directly stimulate DA receptors in the post-synaptic membrane of the striatum and improve motor symptoms in PD patients, and also prevent or delay the onset of motor complications. There are two main types: ergot and non-ergot. two enzymes are required for DA degradation, namely monoamine oxidase (MAO) and catechol monooxygen-site monomethyltransferase.
1.6COMT inhibitor
Catechol-oxygen-site monomethyltransferase (COMT) degrades L-D into 3-monomethyldopa, a toxic inactive substance that may be associated with motor fluctuations and the development of allodynia. COMT inhibitors prolong and increase the bioavailability of L-D, provide a more stable DAergic stimulus, and enhance the efficacy of L-D and also delays the development of motor neuron complications if applied at an early stage. [7] Therefore, it can be clinically applied as an important adjuvant agent in case of drug decay and switching phenomenon after long-term L and D therapy for severe PD, which needs to be combined with L-D to take effect.
Such new drugs are tolcapone and entacapone. Tolcapone is not used alone, but in combination with levodopa drugs to control dyskinesia in PD patients, as well as to treat motor complications in PD patients, improve the end-of-dose phenomenon, increase the “on” period and decrease the “off” period. Entacapone can also be used in combination with levodopa drugs to more effectively control dyskinesia in PD, with good safety and tolerability, and without causing serious liver damage. In addition, entacapone can prevent the increase of homocysteine level in blood caused by levodopa, thus reducing the risk of dementia and cardiovascular disease in PD patients.
2.Neuroprotective treatment
The entry point of neuroprotective therapy is to interrupt the neuronal damage loop at an early stage to prevent neuronal degeneration and apoptosis, slow down the development of PD and improve the patient’s symptoms. The drugs with neuroprotective therapeutic effects currently in clinical use are mainly MAOB inhibitors and DA receptor agonists, while clinical trials of high-dose coenzyme Q10 have also been suggested to have possible neuroprotective effects, but further confirmation is needed. Silegiline (Midobic) can protect DAergic neurons from MPP toxicity by preventing the conversion of MPTP to MPP through antioxidant effects; the anti-apoptotic effect of resagiline is related to the phosphorylation of protein kinase PKC and the Bcl I-2 family. Both sellegran and resagiline improve motor function in early and progressive stages of PD. [3]
3. New targets for drug therapy in Parkinson’s disease
Adenosine A2A receptor antagonists.
a synaptic nucleoprotein inhibitors.
Anti-inflammatory therapy.
4. Therapeutic perspectives of PD
4. 1 Adrenergic receptor antagonists
The a2 adrenergic a-2a and 2ca receptors are widely distributed in the basal ganglia, including the substantia nigra. In primate models made by MPTP, and a-2 receptor antagonists reduce levodopa-induced dyskinesia and prolong the duration of levodopa action J, an antidepressant whose main effect is a-2 receptor antagonist, can reduce levodopa-induced dyskinesia in PD patients.
4, 2 pentraxin reuptake inhibitor (5, HT)
The basal ganglia receive output from the suture nucleus 5, HT, and many other types of 5, HT receptors exist in the striatum and other areas of the basal ganglia. fluoxetine, a 5HT reuptake inhibitor, inhibits levodopa-induced dyskinesia in PD patients.
4, 3 Adenosine A2a receptor antagonists [8]
A2a receptor antagonist KF13837 can alleviate the symptoms of MPTP-induced PD model monkeys, and other drugs of the same type are SCH-58261 and KW6002, which combined with levodopa or dopamine agonists can improve the anti-PD effect but not increase the vulnerability to dyskinesia, and may become a new effective anti-PD drug.
5.Summary
The treatment of Parkinson’s disease (PD) has a variety of options, clinically advocating early treatment, gradual increment, individualized dosing and combination of drugs. the treatment of PD, whether for neurologists, neurosurgeons and drug workers, has been invested with a lot of hard work and has achieved brilliant results, making PD one of the few neurodegenerative diseases for which there are ways to treat.
In addition, further clinical treatment research on this disease is continuing by domestic and foreign scholars, which shows a bright future for the drug treatment of PD. In the future, the key of PD drug therapy research should perhaps be to find new therapeutic targets on the basis of clear etiology and pathogenesis, and to develop novel, highly selective drugs with precise drug action mechanism and less adverse effects for the benefit of PD patients.