Implications of COVID-19 in Parkinson's disease: the purinergic system in a therapeutic-target perspective to diminish neurodegeneration

Abstract

The pathophysiology of Parkinson's disease (PD) is marked by degeneration of dopaminergic neurons in the substantia nigra. With advent of COVID-19, which is closely associated with generalized inflammation and multiple organ dysfunctions, the PD patients may develop severe conditions of disease leading to exacerbated degeneration. This condition is caused by the excessive release of pro-inflammatory markers, called cytokine storm, that is capable of triggering neurodegenerative conditions by affecting the blood-brain barrier (BBB). A possible SARS-CoV-2 infection, in serious cases, may compromise the immune system by triggering a hyperstimulation of the neuroimmune response, similar to the pathological processes found in PD. From this perspective, the inflammatory scenario triggers oxidative stress and, consequently, cellular dysfunction in the nervous tissue. The P2X7R seems to be the key mediator of the neuroinflammatory process, as it acts by increasing the concentration of ATP, allowing the influx of Ca²⁺ and the occurrence of mutations in the α-synuclein protein, causing activation of this receptor. Thus, modulation of the purinergic system may have therapeutic potential on the effects of PD, as well as on the damage caused by inflammation of the BBB, which may be able to mitigate the neurodegeneration caused by diseases. Considering all the processes of neuroinflammation, oxidative stress, and mitochondrial dysfunction that PD propose, we can conclude that the P2X7 antagonist acts in the prevention of viral diseases, and it also controls purinergic receptors formed by multi-target compounds directed to self-amplification circuits and, therefore, may be a viable strategy to obtain the desired disease-modifying effect. Thus, purinergic system receptor modulations have a high therapeutic potential for neurodegenerative diseases such as PD.

Keywords: COVID-19; Free radicals; Neurodegeneration; Parkinson; Purinergic system.

Association between oxidation and inflammation present in Parkinson's and SARS-CoV-2 infection. Association between oxidation and inflammation present in Parkinson's and SARS-CoV-2 infection. The dopaminergic neuron, the substantia nigra and the mitochondria stand out, as well as the Lewy body with the presence of α-synuclein - characteristic of damaged neurons. Several genes that may be involved in the pathophysiology of Parkinson's are analyzed, such as PGC-1α, PINK1, PARK2, PARK7 and PARK8. In the mitochondria, complex I dysfunction and the consequent accumulation of ROS are analyzed. It is observed that mutations of Lewy bodies and α-synuclein protein (α-Syn) cause oxidative stress and an increase in ROS release by mitochondria. P2X7R negatively regulates cellular autophagy triggering processes of apoptosis and ROS increase. All these factors combined contribute to α-synuclein accumulation and neuronal death and can culminate in PD. Thus, SARS-CoV-2 infection causes an excessive and decompensated release of pro-inflammatory markers such as TNF-α and IL-6, causing the cytokine storm and cellular degeneration of the BBB endothelium. The virus replicates in the bloodstream and invades the CNS through three distinct paths explained in the image, one of which uses the macrophages themselves to enter the CNS (Trojan Horse's Strategy). Excess markers, as well as occurring in the BBB endothelium, contribute to neuronal depletion, which can drive the PD neurodegenerative process. In addition, the impairment and damage to the BBB makes it less able to prevent the passage of antigens and SARS-CoV-2 itself to the CNS. Due to the increase in extracellular ATP and through the P2X7R, cascades of reactions that trigger cell death occur, when you have a SARS-CoV-2 infection, the scenario worsens significantly. The activation of these IL-1β and IL-6 of microglial cells occurs with the entry of ATP into the cell that contributes to the progression of the disease.

Fig. 1

The hypothetical role of SARS-CoV-2 in mitochondrial damage and in Parkinson’s disease. SARS-CoV-2 infects individuals, especially through the airways, being able to reach the brain and trespassing the BBB in an easier way. Once the virus is installed in brain structures, such as the substantia nigra in the midbrain, it is capable of developing inflammatory processes in the dopaminergic neurons in this region. Due to the inflammation of the cells, mitochondria are also affected and damaged, resulting in the excessive formation of ROS. The excess of ROS in the dopaminergic neurons generates a degeneration and death of this tissue. As there is a major loss of dopaminergic neurons, the liberation of dopamine in the midbrain is reduced and compromised, inducing or worsening cases of Parkinson’s disease

Fig. 2

Current status of Parkinson’s disease treatment. This therapeutic process has three main aspects: a pharmacological, b surgical, and c rehabilitation. Regarding drug treatment, MAO-B inhibitors are traditionally used, such as selegiline and safinamide, which are dopamine metabolism regulators. Also, it is very common to use Carbidopa and Levodopa to increase dopamine in the central nervous system. In addition, surgical interventions are used to improve patients’ quality of life. Finally, many patients are referred to physical therapy, in the search for improvement of verbal and motor symptoms, such as Lee Silverman Voice Treatment (LSVT)

Fig. 3

Role of P2X7 in the progression of PD in its association pathways with the SARS-CoV-2 virus. Neuroinflammation prior to neurodegeneration, potentiated by SARS-CoV-2 infection, causing cell lysis and increased extracellular ATP. This cycle feeds back, and the increase in ATP in the extracellular environment can also accelerate neurons impairment and death, triggering a series of inflammatory cascades through interleukins and mitochondrial and lysosomal dysfunctions. It is observed that mutations in Lewy bodies and α-synuclein (α-syn) protein trigger a decrease in AMPK phosphorylation, which is activated to regulate cellular energy metabolism, generating oxidative stress and an increase in the release of ROS by the mitochondria. Another factor related to the decrease in AMPK phosphorylation is that P2X7R negatively regulates cellular autophagy, triggering processes of apoptosis and ROS increase. Pericytes also influence the formation of ROS, and when the maintenance of phagocytosis is unregulated, this cell participates in the neuroinflammation process. Otherwise, with the entry of ATP, the activation of IL-1β and IL-6 of microglial cells that triggers the activation of the NLRP3 inflammasome that induces pyroptosis (programmed death) and consequently promotes even more release of IL-1β. Both the NLRP3 inflammasome and the dysregulation of the lysosome in the progression of COVID-19, the inflammasome acts as a trigger of the cytokine storm, leaving it very susceptible to the aggravation, whereas in the lysosome, the coronaviruses interact with the cellular autophagy pathway to increase the replication of the virus. The cytokine storm caused by COVID-19 increases the release of extracellular ATP that is regulated by P2X7R. In this way, P2X7R antagonists can be targeted to modulate inflammatory pathways and reduce neurodegenerative effects