By Sabino Méndez Pastor
Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease. It is a progressive motor disorder characterised by resting tremors, rigidity, difficulty in walking (Parkinsonian gait) and a decrease in movement known as hypokinesia that ranges from bradykinesia (slowness in the initiation of voluntary movements) to akinesia (loss of movements) (Hayes, 2019). Many patients also suffer from non-motor symptoms that include autonomic, psychiatric and cognitive deficits such as depression and dementia (Sarkar, Raymick and Imam, 2016). It is estimated that PD affects 4 million people worldwide and its prevalence is expected to grow as the life expectancy increases and the population of developed countries ages (Hayes, 2019). Therefore, effective treatments are necessary to treat this debilitating disorder and improve the quality of life of patients.
In healthy individuals, the thalamus is responsible for initiating movements by activating the motor cortex. The thalamus is normally under tonic inhibition and regulated by the basal ganglia. Activation of the direct pathway in the basal ganglia releases the thalamus from this inhibition which enhances the output of the motor cortex to facilitate movements (Calabresi et al., 2014). In PD, aggregation of toxic proteins in Lewy bodies results in the death of dopaminergic neurons in one of the basal ganglia: the substantia nigra. The neurons in the substantia nigra produce dopamine to regulate both the cortex and thalamus. Thus, reduction of the dopamine release from this area impairs the thalamic excitation of the cortex which leads to the motor impairments characteristic of PD (Hayes, 2019).
For this reason, the main approach currently used to treat PD are dopamine replacement therapies to restore the function of the basal ganglia circuitry. The most effective and commonly used consists in the administration of levodopa (L-DOPA), a dopamine precursor that can cross the blood-brain barrier (contrarily to dopamine) and is converted into dopamine by neurons within the substantia nigra. This makes up for the dopamine deficiency, providing symptomatic relief. However, only 25% of patients treated with this agent show a good response after 5 years. To overcome this problem dopamine agonists can be used alone or in combination with L-DOPA as they do not depend on enzymatic activation and have long lasting therapeutic effects. Another group of dopamine related agents used to complement L-DOPA are inhibitors of catechol-O-methyltransferase, an enzyme that degrades L-DOPA, to increase its lifetime and amount available. Dopamine replacement therapies present however some important adverse effects including nausea, psychosis, hallucinations, and hypotension (Hayes, 2019).
Deep brain stimulation (DBS) has proved to be an effective approach for treating PD. In the DBS procedure, electrodes are implanted into either the subthalamic nucleus or the internal globus pallidus which are both basal ganglia nuclei. The substantia nigra normally regulates these nuclei but its degeneration in PD leads to excessive output of the later which ultimately inhibits the motor cortex’s output. DBS has been documented to restore the tonic pattern of the subthalamic nuclei and internal globus pallidus, alleviating the symptoms of PD. DBS also involves adverse effects, with studies suggesting that it may cause manic depression, induce emotional instability and suicidal thoughts (Hayes, 2019).
The drawbacks of the therapies currently used to treat PD symptoms have led to extensive research on alternative treatments for this neurodegenerative disorder. The adenosine A2A receptor (A2AAR) has been proposed as an attractive target for non-dopaminergic therapy. In healthy individuals, dopamine release from the substantia nigra activates D2 receptors in the striatum (another basal ganglia). This lowers the firing of striatum neurons which ultimately enhances the activation of the cortex to facilitate the initiation of movements. In PD, the absence of such regulation results in hypokinesia. The striatum is also the region of the mammalian body with the highest expression of A2A receptors. In vitro studies have shown that activation of these receptors by A2AAR agonists decrease the affinity of dopamine for D2 receptors. In vivo administration of A2AAR antagonists increased the effects of D2 receptor agonists in the rat striatum. Other studies on animal models of PD confirmed that A2AAR antagonism improves motor activity by reducing the postsynaptic effects of dopamine depletion (Nazario, da Silva and Bonan, 2017). Although A2AAR antagonists have not been found to be more effective than L-DOPA therapy, co-administration of these agents induced a reduction of the side effects of L-DOPA, namely of the occurrence of uncontrolled and involuntary movements (dyskinesia) (Hayes, 2019). Istradefylline is the only A2AAR antagonist that has been approved as an adjunctive therapy to L-DOPA and exclusively in Japan. The results of clinical trials for this agent have not shown to provide enough protective effects to obtain approval in the US or the EU but other clinical trials are being carried on to test the efficacy of other A2AAR antagonists (e.g. Tozadenant) (Nazario, da Silva and Bonan, 2017; Franco and Navarro, 2018).
Although PD is mostly associated with dopamine depletion, neuroinflammation is another key feature of the neurodegenerative disease. PD patients show increased levels of proinflammatory cytokines in the cerebrospinal fluid and basal ganglia and of macrophage activation in the brain. Activated macrophages may release more chemicals that are toxic to cells as in vitro and in vivo studies have shown that non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin or ibuprofen can prevent the degeneration of dopaminergic neurons. In addition, epidemiological studies have demonstrated that regular intake NSAIDs can reduce the risk of having PD by around 45% (Hayes, 2019).
Minocycline, an anti-microbial commonly used to fight infections, has been shown to prevent apoptosis in vitro and to inhibit activation of brain macrophages. In vivo studies have confirmed a neuroprotective role of this agent alone or combined with other anti-parkinsonian drugs although clinical studies have failed to show that it induces protection against PD (Cankaya et al., 2019).
In conclusion, Parkinson’s disease is a debilitating condition and an increasingly important global health issue that needs more research as the current treatments are not always effective and present significant side effects. Many promising approaches to alleviate PD symptoms more effectively are arising such as the use of adenosine receptor agonists, NSAIDs and minocycline. However, further well-designed clinical studies with larger number of patients are required to confirm with accuracy the efficiency of these treatment candidates and their possible adverse effects.
References:
Calabresi, P. et al. (2014) ‘Direct and indirect pathways of basal ganglia: A critical reappraisal’, Nature Neuroscience. Nature Publishing Group, pp. 1022–1030. doi: 10.1038/nn.3743.
Cankaya, S. et al. (2019) ‘The therapeutic role of minocycline in Parkinson’s disease’, Drugs in Context. Bioexcel Publishing LTD. doi: 10.7573/dic.212553.
Franco, R. and Navarro, G. (2018) ‘Adenosine A2A receptor antagonists in neurodegenerative diseases: Huge potential and huge challenges’, Frontiers in Psychiatry. Frontiers Media S.A., p. 12. doi: 10.3389/fpsyt.2018.00068.
Hayes, M. T. (2019) ‘Parkinson’s Disease and Parkinsonism’, American Journal of Medicine. Elsevier Inc., pp. 802–807. doi: 10.1016/j.amjmed.2019.03.001.
Nazario, L. R., da Silva, R. S. and Bonan, C. D. (2017) ‘Targeting adenosine signaling in Parkinson’s disease: From pharmacological to non-pharmacological approaches’, Frontiers in Neuroscience. Frontiers Media S.A., p. 658. doi: 10.3389/fnins.2017.00658.
Sarkar, S., Raymick, J. and Imam, S. (2016) ‘Neuroprotective and therapeutic strategies against Parkinson’s disease: Recent perspectives’, International Journal of Molecular Sciences. MDPI AG. doi: 10.3390/ijms17060904.
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