**4. Targeted therapies for Parkinson's disease**

Till date, no specific curative therapy is available for PD. There are two main approaches such as protective therapy and symptomatic therapy that have been practiced for the treatment of PD. Under symptomatic therapy, anticholinergic agents and some dopamine analogs help to restore the dopamine levels and result in improvement of the movement disabilities. Though, anticholinergic agents cause some serious effects on central nervous system such as cognitive impairment and hallucination along with constipation and dryness of mouth. In the field of PD management Levodopa brought a revolution by improving quality of life, parkinsonian symptoms, and normalizing life expectancy [44]. Other recent dopaminergic therapies, such as monoamine oxidase B inhibitors, dopamine agonists, catechol-O-methyltransferase inhibitors, and other unique formulations of levodopa, have also been developed to address parkinsonian symptoms [44, 45]. Continuous duodenal infusion of levodopa/ carbidopa intestinal gel and apomorphine subcutaneous pumps are used to overcome the levodopa shortcomings. On the other hand, as PD pathogenesis mainly deals with oxidative damage, protective therapy that has free radical scavenging properties helps to reduce the side effects of drugs. Selegiline, bromocriptine, ropinirole, pramipexole, and vitamin E fall under this category [46].

Moreover, deep brain stimulation (DBS) is considered a very useful approach for patients with motor complications [47]. All these therapies have been of great value in the PD symptoms management in patients who are not responsive to medication. Currently, development of PD treatments majorly depends upon development and application of biomarkers that will help to improve the target engagement, disease state, safety, and disease outcome [48]. The development of new genetic editing technologies can open the possibility to correct mutated genes and regulatory DNA in the monogenic forms of PD [49–51]. Several methods of gene delivery that include use of viral vectors and CRISPR as well as the process of genome editing have been developed to manage PD symptoms. Currently, clinical trials of Gene therapy in PD have tried to focus on 4 main targeted approaches such as restoring dopamine synthesis, neuroprotection, genetic neuromodulation, and addressing disease-specific pathogenic variants [52].

To prevent the neurodegeneration of dopaminergic neurons by the overexpression of neurotrophic factors (NTF) is considered as a powerful strategy in PD management. The delivery of these factors, such as the glial cell line-derived neurotrophic factor (GDNF), neurotrophic factor (NF), cerebral dopamine neurotrophic factor (CDNF), neurturin (NRTN), and growth/differentiation factor 5 (GDF5) by the use of recombinant viral vectors to enable long-term expression might open a new way in PD management [53].

Even experimental studies have shown that down-regulation of α-syn levels by gene silencing with RNA interference (RNAi) can be beneficial in the normalizing expression of α-syn and improving motor function, though balance is important to avoid nigrostriatal neurotoxicity caused by excess downregulation. At epigenetic

level, DNA methylation at SNCA intron1 acts as a regulator of the α-syn transcription, and thus it can consider a target for tight control of α-syn expression. In recent times, active immunization approaches are involved to develop vaccines targeting either the N or C-terminal of α-syn or its aggregation forms. Extensive clinical trials on these advanced techniques are required to prove their efficacy against PD symptoms [54].

#### **4.1 In silico studies and prediction of therapeutic drug**

In the absence of extensive experimental and pharmacological studies, none of the drug candidates are recommended for human use. Molecular docking or in silico studies is the answer to the problem with good potential tool in drug development. Molecular docking is an early guidance tool in contemporary drug discovery that minimizes not only time but also resource. In some cases, scientific data shows that the prediction results based on in silico studies are comparable with in vitro and in vivo results [55]. Molecular docking studies depend upon on joining of a particular ligand to a receptor region, providing information about orientation, conformation, and organization at the receptor site [55]. Nowadays, studies using computational chemistry have been done to predict potential inhibitors for neurodegenerative diseases from flavonoid derivatives [39]. During the pandemics or for the disease like PD or AD alternative food-based medicine or the flavonoids or bioactive compounds from the plant can be considered as the good alternatives. Development of the drug from the plant bioactive compound depends upon a great deal of in silico molecular docking investigation.

*In silico* studies, involving Parkinson's disease and anti-inflammatory activity of novel bioactive compounds such as quercetin, epigallocatechin gallate (EGCG), and acacetin have been done to predict inhibitory activities against the enzyme α-synuclein. According to other studies involving flavonoids including morin, naringenin, taxifolin, esculatin, daidzein, genistein, scopoletin, galangin, and silbinin have proven their inhibitory effect against lipoxygenase enzyme. Moreover, data using karanjin against several protein targets in relation to AD and PD have shown their efficiency in management of PD. Ligand-based-virtual screening together with structure-based virtual screening (docking) can be done to prove the efficiency of plant-based bioactive compounds, like alkaloids or flavonoids as inhibitors of PD- or AD-related proteins [56–58].

#### **4.2 Treatment of Parkinson's disease and its impact on SARS-CoV-2 infection**

Till now, no specific medicine is available to treat the SARS-CoV-2 infection. Nowadays, drug repurposing by the in silico studies is an essential technique for quick identification of frontline weapons to combat COVID-19. Antiviral and other lifesaving drugs are trying to repurpose for the treatment of COVID-19 as SARS-CoV-2 replication shows a variety of clinical symptoms. Some of them are investigated to block different steps of host tropism such as transmembrane serine protease 2 (TMPRSS2), and/or viral entrance through the ACE2 receptor, viral membrane fusion, endocytosis, the activity of the SARS-CoV-2-3-chymotrypsin-like protease, etc. Treatment options for various diseases linked with COVID-19 such as obesity, sleep apnea, Parkinson's disease, and Alzheimer's disease have markedly changed during the pandemic. FDA-approved drug levodopa is mainly involved in alteration in dopamine synthetic pathways but studies have shown its involvement in the pathophysiology of SARS-CoV-2. DDC inhibitors act upon *DDC* and also *ACE2*, the gene encoding, the main receptor to SARS-CoV2. On the other hand, dopamine agonists

*COVID-19 and Its Impact on Onset and Progression of Parkinson's and Cognitive Dysfunction DOI: http://dx.doi.org/10.5772/intechopen.105667*

are found to have detrimental effects on patients with PD symptoms and positive for the COVID-19. As per a study, a small number of COVID-19-positive PD patients were prescribed to take amantadine but did not manifest symptoms of the disease. Furthermore, COMT inhibitors like entacapone have shown potential effects against the virus SARS-CoV-2, when interactome analysis of potential drug repurposing studies was done [59, 60].

### **5. Conclusion**

Since the beginning of the pandemics, SARS-CoV-2 has become one of the main research interests, especially due to high mortality rates among different populations and its catastrophic impact on global healthcare as well as socio-economic condition. Like other members of the Coronaviridae family, SARS-CoV-2 also has neurotropic properties. The harmful effects of the virus seem to exert either in a direct manner—by spreading through gastrointestinal nervous and/or olfactory pathways, or by evoking an inflammatory response. Along with the inflammatory response, the pathophysiology of COVID-19 also involves the complement and the coagulation systems. These triad systems interact with each other and show detrimental effects like appearance of the cytokine storm in ARDS. This leads to multisystem failure, especially in the case of disseminated intravascular coagulation disorders. In both cases – prodromal PD and COVID-19 induced PD. Parkinsonism is majorly associated with motor dysfunction, the hyposmia and hypogeusia. The cytoplasmic alpha-synuclein accumulation is associated with neurodegeneration in the nigrostriatal system of PD-affected patients [6, 8].

As SARS-CoV-2 may have a trigger for blood-brain barrier impairment and gain direct access to brain regions, the N-protein of the virus may play a major role in PD pathogenesis. Interaction between viral N-protein and alpha-synuclein promotes formation of amyloid fibril and hallmark of Parkinson's. There is a broad spectrum of COVID-19-related symptoms, perhaps associated with either pre-existing conditions or the presence of T cells that are reactive to previous coronavirus infections or in part of viral entry points. The neurological manifestations may be involved with capillaries inflammation, hypoxemia, the blood-brain barrier, and thrombosis that act as triggers for seizures or ischemic or hemorrhagic strokes. Production of pro-inflammatory cytokines and chemokines by activated microglia, astrocytes, or mitochondrial dysfunction in glial cells is considered as a major contributor to neuroinflammation. The crosstalk between these contributors may induce α-syn accumulation mediated neurodegeneration in α-synucleinopathies. This crosstalk mechanism may be considered a favorable target for α-synucleinopathy-associated neurodegenerative disease treatment [17, 18, 24]. Due to various impeding factors, such as limited understanding of the neurodegeneration mechanisms in PD, the heterogeneity of the pathology, absence of reliable biomarkers to diagnose the pathology, and the lack of adequate animal models, the development of effective preventive or curative therapies for PD has become extremely challenging. Though some medicine and therapy are available for the management of PD, they have severe detrimental effects on the central nervous system. Molecular docking or in silico studies are good potential tools in drug development for repurposing the drug or identification of new plant-based bioactive with potential neuroprotective activity. Shortly, by using this technology it will be possible to develop broad-spectrum, novel drugs active against not only a larger array of coronavirus but also will be the ultimate treatment strategy for circulating and emerging COVID-related neurological manifestations.
