Targeting Neurological Manifestations of Coronaviruses by Candidate Phytochemicals: A Mechanistic Approach

The novel coronavirus 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has made a wide range of manifestations. In this regard, growing evidence is focusing on COVID-19 neurological associations; however, there is a lack of established pathophysiological mechanisms and related treatments. Accordingly, a comprehensive review was conducted, using electronic databases, including PubMed, Scopus, Web of Science, and Cochrane, along with the author’s expertize in COVID-19 associated neuronal signaling pathways. Besides, potential phytochemicals have been provided against neurological signs of COVID-19. Considering a high homology among SARS-CoV, Middle East Respiratory Syndrome and SARS-CoV-2, revealing their precise pathophysiological mechanisms seems to pave the road for the treatment of COVID-19 neural manifestations. There is a complex pathophysiological mechanism behind central manifestations of COVID-19, including pain, hypo/anosmia, delirium, impaired consciousness, pyramidal signs, and ischemic stroke. Among those dysregulated neuronal mechanisms, neuroinflammation, angiotensin-converting enzyme 2 (ACE2)/spike proteins, RNA-dependent RNA polymerase and protease are of special attention. So, employing multi-target therapeutic agents with considerable safety and efficacy seems to show a bright future in fighting COVID-19 neurological manifestations. Nowadays, natural secondary metabolites are highlighted as potential multi-target phytochemicals in combating several complications of COVID-19. In this review, central pathophysiological mechanisms and therapeutic targets of SARS-CoV-2 has been provided. Besides, in terms of pharmacological mechanisms, phytochemicals have been introduced as potential multi-target agents in combating COVID-19 central nervous system complications.


INTRODUCTION
Phylogenetic studies on the genomic structure, introduced various types of coronaviruses (CoVs), including NL63, 229E, OC43, HKU1, middle east respiratory syndrome (MERS)-CoV, severe acute respiratory syndrome coronavirus (SARS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Gurung et al., 2020a;Vellingiri et al., 2020), divided into four groups of alpha (229E and NL63), beta (OC43 and HKU1), gamma and delta coronaviruses. Among coronaviruses, alpha and beta groups cause respiratory manifestations in human (Gurung et al., 2020b;Gurung et al., 2020c;Rasool et al., 2020). Recently, a new strain of coronaviruses, namely SARS-CoV-2 has been found, belonging to a distinct class of beta coronaviruses (Divani et al., 2020). SARS-CoV-2 made a deadly disease, termed coronavirus disease 2019  with devastating manifestation all over the world (Fitriani et al., 2020;Nemoto et al., 2020). The large and positive sense RNA genome with a size of 27-32 kb, as well as an envelope with spike (S1 and S2)/conjugated proteins (Holmes and Lai, 1996;Davidson et al., 2020) are associated with COVID-19 symptoms over a period of 2-14 days. Studies have revealed that when viruses enter to the lung tissue cells and proliferate, cause alveolar and interstitial inflammatory secretion and edema that leads to alveolar gas exchange impairment and hypoxia in the central nervous system (CNS), thereby increases anaerobic metabolism in the mitochondria of brain cells (Wu et al., 2020c). Besides, SARS-CoV enters the nasal passage and triggers neural inflammatory responses through dysregulation of the immune system. The entry factors for SARS-CoV-2 are highly expressed in nasal epithelial cells (Sungnak et al., 2020). As a consequence, CoVs enters the brain via the olfactory tract in the early stages of nasal vaccination or infection (Mori, 2015;Wu et al., 2020c;Desforges et al., 2020). Accordingly, this virus is not limited to the respiratory system but invades peripheral nerves and enters the CNS then causes/aggravates neurodegenerative disorders (Matsuda et al., 2004;Vellingiri et al., 2020). Research has shown the presence of SARS-CoV in cortex, hippocampus, spinal cord, brain stem, cerebellum, striatum, colliculus superior, and hypothalamus (Jacomy and Talbot, 2003). Consequently, COVID-19 patients have shown neurological symptoms, including headache, dizziness, hypogeusia, nausea, vomiting, and anosmia (Ahmad and Rathore, 2020;Vellingiri et al., 2020).
From the pathophysiological point of view, the spike protein in the morphology of COVID-19 bind to angiotensin-converting enzyme (ACE)-receptors on alveolar epithelial cell type 2 (AT2), primed by transmembrane protease serine 2 (TMPRSS2) to allow coronavirus entry (Marchetti et al., 2018;Li et al., 2019b;Wang et al., 2020b;Vallamkondu et al., 2020). Experimental evidence indicated that COVID-19 enters the lung via the respiratory tract and invades AT2 cells to generate a surfactant regarding declining related tension within alveoli to alleviate collapsing pressure. Also, ACE2 is presented in kidney, heart, enterocytes, pancreas, endothelial cells and widely distributed in brain to facilitate the SARS-CoV-2 entry into the cells (Li et al., 2003;Diao et al., 2020). The neural distribution of ACE2 was controversial at first. While a quantitative real-time RT-PCR study showed low levels of ACE2 mRNA in the human brain (Harmer et al., 2002), immunohistochemistry results indicated that ACE2 protein expression was restricted to arterial and endothelial smooth muscle cells (Hamming et al., 2004). Additionally, the predominant expression of ACE2 in glial cells was shown in brain primary cell cultures (Gallagher et al., 2006). Complementary evidence showed the widespread presence of ACE2 mRNA and protein throughout the brain (Doobay et al., 2007) or brainstem (Lin et al., 2008). Finding SARS-CoV in brains of infected patients also confirmed related distribution of ACE2 (Ding et al., 2004;Gu et al., 2005;Xu et al., 2005;Xia and Lazartigues, 2008).
Unfortunately, up to now there is no antiviral drug or vaccine for the treatment of coronaviruses infection, although candidate phytochemicals can be promising factors with antiviral potentials for the treatment of infection Gurung et al., 2020b). Some previous research has indicated neurological manifestations in coronaviruses (Ahmed et al., 2020;Yavarpour-Bali and Ghasemi-Kasman, 2020). Besides, limited studies suggested natural products and candidate phytochemicals as helpful agents for the prevention and treatment of coronaviruses (Hasan et al., 2020;Majnooni et al., 2020;Zhou and Huang, 2020). In this study, an extensive review was performed on neurological manifestations of coronaviruses, as well as the effects of candidate phytochemicals on the aforementioned signaling pathways. Additionally, this is the first review on highlighting phytochemicals with antiviral and neuroprotective effects, which targets the neural pathogenic pathways of CoVs (termed candidate phytochemicals) regarding the prevention and treatment of COVID-19 neuronal signs.

STUDY DESIGN
We used electronic databases (e.g., Scopus, PubMed, Medline, and Web of Science) and related articles in other sources, to conduct a comprehensive review on the neurological manifests of coronaviruses, as well as the phytochemicals effects. The keywords ("Severe Acute Respiratory Syndrome" OR "SARS" OR "Middle East Respiratory Syndrome" OR "MERS" OR "Coronavirus disease 2019" OR "COVID-19" OR "SARS-CoV" OR "SARS-CoV-2") AND ("neurological sign" OR "neurological manifestation" OR "neuron" OR "nerve" OR "central nervous system" OR "CNS" OR "brain" OR "neurology" OR "neuropathy" OR "stroke" OR "multiple sclerosis" OR "encephalitis" OR "encephalopathy") [title/abstract/keywords] were used. All the phytochemicals possessing both the antiviral and neuroprotective activities with the keywords ("phytochemical" OR "secondary metabolite" OR "plant" OR "polyphenol" OR "phenolic compound" OR "flavonoid" OR "alkaloid" OR "terpen" OR "terpenoid" OR "quinone") were also searched in the whole text. Overall, the phytochemicals with reported antiviral and neuroprotective effects possessing the potential of modulating coronaviruses pathophysiological mechanisms were included. Data were collected without language and date restrictions until October 2020. The screening of retrieved articles was also done. on the reference lists/citation. Regarding completing review on the electronic databases, hand searching also was done relying on the authors' expertize on the SARS-CoVs pathophysiological mechanisms in CNS and candidate phytochemicals.
Severe respiratory syndrome as one of the critical impairment of COVID-19 may result in systemic hypoxia, hypercarbia, and anaerobic metabolism resulting in neuronal swelling and brain edema/damage (Suri et al., 2020). SARS-CoV-2 also invades to the spinal cord and causes acute inflammation of gray and white matter in the spinal cord (myelitis), which was recognized by the acute flaccid myelitis of lower limbs, urinary and bowel incontinence . Evidence has shown a close relationship between COVID-19 and Parkinson disease, increased motor symptoms (e.g., tremor), freezing of gait or dyskinesias, and declined the efficacy of dopaminergic medication (Macht et al., 2007;Zach et al., 2017;Ehgoetz Martens et al., 2018). Interestingly, it seems to be a near linkage between dopamine synthesis pathway and COVID-19 pathophysiology. In this line, dopa decarboxylase, as a regulatory enzyme in dopamine pathway is meaningfully co-expressed with ACE2 receptor. On the other hand, SARS-COV virus downregulates ACE2 in consistent with dopamine synthesis alteration (Kuba et al., 2005). Besides, as dopamine is expressed in the alveolar epithelial cells, it also contributes in lung immunity, as well as what ACE2 does (Bone et al., 2017). Accordingly, considering the critical role of dopamine deficiency in Parkinson's disease, the SARS-CoV-2 virus may cause such sporadic signs COVID-19 patients (Rietdijk et al., 2017).
Additionally, evidence indicated that CoVs may play an essential function in the pathogenesis of multiple sclerosis (Saleki et al., 2020). The CoVs isolated from multiple sclerosis patients were neutralized using the patients' serum. This revealed the destructive role of CoVs in the pathogenesis of multiple sclerosis (Burks et al., 1980). Growing studies are evaluating the use of immunomodulatory/disease-modifying agents in multiple sclerosis patients with COVID-19. Results declared an increased risk of COVID-19 complications in those treated patients (Baysal-Kirac and Uysal, 2020;Ramanathan et al., 2020). Decision on continuing/stopping the immunotherapy in these patients is closely dependent on disease severity and activity (Giovannoni et al., 2020).
Orsucci and co-others have revealed that there are olfactory and gustatory function impairments as common neural disorders in patients of COVID-19 (Orsucci et al., 2020). It has shown in CNS-CoV disease, there is a lower level of lymphocytes, eosinophils and a higher level of neutrophils as well as monocyte (Saleki et al., 2020). Also, Toscano et al. observed Guillain-Barré syndrome, lower limb weakness and paresthesia, facial diplegia followed by ataxia and paresthesia, flaccid tetraparesis or tetraplegia in COVID-19 (Toscano et al., 2020). Researchers in several cases observed tonic-clonic seizure, anxiety, psychotic symptoms, meningeal irritation signs, extensor plantar response, encephalitis, dysphagia, dysarthria, bulbar impairment and massive hemorrhagic conversion .

THE PATHOPHYSIOLOGICAL MECHANISTIC PATHWAYS OF CORONAVIRUSES IN CENTRAL NERVOUS SYSTEM
Experimental evidence has indicated that coronaviruses invade to neurons and glial cells to induce an unfolded protein response (UPR) regarding necroptosis in neuronal cells (Meessen-Pinard et al., 2017). As previously mentioned, coronaviruses caused neuronal damages and death along with related neuroinflammatory responses (Morfopoulou et al., 2016). There are multiple mechanisms by which SARS-CoV-2 enters the CNS and causes associated complications. Those mechanisms are blood-mediated contamination (hematogenous), neuronalmediated infection (neurogenic), immunodeficient related damage, direct respiratory infection, and hypoxic injury (Ahmed et al., 2020) which are described as following. During the hematogenous manner, CoVs crossed the blood-brain barrier (BBB) and entered the brain. This occurs via two mechanisms, by direct penetration of the virus particle crossing the BBB or by hijacking peripheral blood cells (Bohmwald et al., 2018). In the latter way of invasion, Human coronavirus OC43 (HCoV-OC43) accesses the CNS via the neurogenic way to be appeared in the cell bodies and dendrites of olfactory neurons, then spread in hippocampus, cortex and spinal cord (Niu et al., 2020a). During the viremia phase of illness, BBB disruption causes a direct virus entrance to the brain. Spreading/disseminating of SARS-CoV-2 from the cribriform bone in nearby proximity to the olfactory bulb, and brain causes in seven days (Baig et al., 2020).
Besides, peripheral invasion of nerve terminals by CoVs through the connected synapse leads to the virus entry to the CNS (Ahmad and Rathore, 2020). Additionally, systemic hypoxia resulted from severe pneumonia causes vasodilatation, anaerobic metabolism, hypoxia and accumulation of toxic compounds lead to brain damage (Tu et al., 2020).
As previously mentioned, studies have suggested several mechanisms for entering the SARS-CoV-2 to the nervous system, although the exact mechanism is not clear (Yavarpour-Bali and Ghasemi-Kasman, 2020). Scientists have suggested that coronaviruses enter the olfactory bulb/ epithelium, then penetrates to CNS. So, make the anosmia or hyposmia as the neural manifestation of COVID-19. Recently additional studies have suggested different mechanisms for anosmia in COVID-19, such as olfactory cleft syndrome, mucosal obstruction, direct damage of olfactory sensory neurons, impairment of the olfactory perception center and cytokine storm in the brain (Yazdanpanah et al., 2020). Released inflammatory factors altered the penetrance of the BBB and increased inflammatory cascade (Singhi, 2011). Studies have also shown that deficiency in neuronal endoplasmic reticulum (ER) leads to the activation of UPR-induced by SARS-CoV (Chan et al., 2006;Ron and Walter, 2007). Until now, some related signaling pathways have shown functional roles in the UPR processing, such as ATF6, phospho-extracellular signal-regulated kinase (p-ERK)/eIF2-alpha and IRE1/XBP1 (Ron and Walter, 2007). Favreau et al. indicated that HCoV-OC43 induced UPR and causes neuronal death by caspase-3 activation and nuclear fragmentation (Favreau et al., 2009). From another mechanistic point, studies suggested that SARS-CoV-2 induces severe inflammation that leads to thrombosis. SARS-CoV-2 also binds to toll-like receptors (TLR) and causes the synthesis and liberation of IL-1. As a matter of fact, TLRs activate biochemical cascade by inflammasome activation as well as type I interferon (IFN) which is released as an important player against viral infection (Marchetti et al., 2018;Conti et al., 2020;Vaninov, 2020).

ROLE OF RENIN-ANGIOTENSIN SYSTEM IN THE NEURONAL MANIFESTATIONS OF CORONAVIRUSES
It has been shown that SARS-CoV-2 mainly enters the CNS via the ACE2 or TMPRSS2 receptors. These receptors are expressed in the glial cells of brain/spinal cord and thereby facilitates the invasion of coronavirus to the spinal cord, which is essential for the host cell entry of SARS-CoV-2 and also plasma membrane fusion (El Tabaa and El Tabaa, 2020; Nemoto et al., 2020). Also, it has been indicated that when coronavirus enters the cells, ACE2 will break and shed by ADAM Metallopeptidase Domain 17 (ADAM17) into the membrane space (Li and De Clercq, 2020). Studies suggested that phosphorylation of ACE2 at Ser680 inhibits ubiquitination of ACE2 and also increase related membrane expression (Amraei and Rahimi, 2020). It has been indicated that renin-angiotensin system (RAS), including angiotensin II (Ang II), ACE, ACE2, angiotensin type-1 receptor (AT1R), angiotensin type-2 receptor (AT2R), and Mas receptor (MAS), plays critical physiological functions. Research suggested that Ang II prevents COVID-19 infection through binding to ATR1 and activating ACE2 internalization, then declining ERK1/2 and p38 mitogenactivated protein kinase (MAPK) pathway (Koka et al., 2008;Fernandes et al., 2011;Divani et al., 2020). Recent reports indicated that Ang II act via two G protein-coupled receptors (GPCR) such as AT1R, angiotensin type-2 receptor (AT2R) which expressed in human lung tissue. Besides, the activations of Ang II can be mediated by AT1R through enhancing several signaling pathways such as MAPK/ERK, IP3/diacylglycerol, tyrosine kinases, and NF-κB (Balakumar and Jagadeesh, 2014;El Tabaa and El Tabaa, 2020). In a parallel way, AT1 stimulates monocytes, macrophages and vascular smooth muscle cells to generate TNF-α and IL-6 (Balakumar and Jagadeesh, 2014). Additionally, Ang II promotes vasoconstriction, released pro-inflammatory cytokine, vascular endothelial dysfunction, and platelet aggregation (Nakashima et al., 2006;Shatanawi et al., 2011). There is also a relationship between Ang II and endothelin-1 (ET-1). Indeed ET-1 has an important function in Ang II-induced endothelial dysfunction and platelet activation through inducing IL-6 release (Touyz and Schiffrin, 1993;Browatzki et al., 2000). In order to reduce SARS-CoV-2 entry and related side effects, ACE2 activity should be declined. It has been found that ACE2 is a critical enzyme in the RAS, which has a critical function role in the human body. In this pathway, renin generated in the kidneys cleaves angiotensinogen from the liver, producing Ang I and then is cleaved by ACE into Ang-II (the substrate of ACE2). Ang I binds to the AT1R and AT2R as well as the RAS system has an important function in SARS-CoV-2 infection (Battagello et al., 2020).
In addition to the critical role of blood, hypoxia, ACE2, neuroinflammation in the neuronal pathogenesis of COVID-19, modulating RdRP/3-chymotrypsin-like protease (3CLpro) and papain-like protease (PLpro), as critical enzymes involved in the replication of SARS-CoV-2, is of great importance. There are also several receptors, namely CD209L (L-SIGN), CD209 (DC-SIGN), neuropilin receptors (NRPs), and CD147/Basigin, which facilitate SARS-CoV-2 entry (Amraei and Rahimi, 2020). As described, there is a close interconnection between the aforementioned dysregulated signaling pathways. In this line, providing multi-target agents capable of a simultaneous modulation of the aforementioned targets could pave the road against COVID-19 neurological manifestations.

IMPORTANCE OF NATURAL PRODUCTS IN COMBATING COVID-19 GENERAL MANIFESTATIONS
The widespread pandemic of COVID-19 disease, by infecting millions of people, and thousands of killing around the world, has triggered researchers to make a diligent effort regarding finding potential drugs or vaccines against SARS-CoV-2. However, these efforts have not yet reached credible drugs due to the inherent complexity of the SARS-CoV-2 pathogenicity/complications . Due to their simultaneous effects on multi-therapeutic targets and low side effects, phytochemicals including alkaloids, flavonoids, polyphenols, quinones, and terpenoids are of the most promising options for finding effective treatment against SARS-CoV-2 (Efferth and Koch, 2011;Mani et al., 2020).
Recent studies showed that three main targets, including main proteases, as well as S protein interaction with ACE2, have attracted the most attention of researchers to discover effective drugs against SARS-CoV-2 from phytochemicals. Additionally, phytochemicals potentially target neuroinflammation to combat related neuronal signs in COVID-19.

POTENTIAL OF PHYTOCHEMICALS AGAINST COVID-19 NEUROLOGICAL ASSOCIATIONS
Recently, no drug or vaccine has been developed for the treatment/prevention of SARS-CoV-2. Phytochemicals have shown to play critical antiviral biological activities and health benefits in CNS (Kähkönen et al., 1999). As previously mentioned, there are several major targets for phytochemicals against coronavirus such as ACE2, spike protein, TMPRSS2, 3CLpro, RdRp and PLpro, which among them ACE2 plays an important role regarding the initial stage of SARS-CoV-2 invasion into the cells/neurons (Huang et al., 2020b). Also, 3CLpro and PLpro play vital roles in SARS-CoV-2 maturation and replication (Xue et al., 2008;Ryu et al., 2010a).
The potential of phytochemicals in suppressing neuroinflammation induced by SARS-CoV-2 has also made them promising agents in combating neuronal signs of COVID-19. As previously mentioned, hyper-inflammation is one of the critical neuropathological mechanisms of SARS-CoV-2 in line with the release of IL-2, IL-6, IL-7, IL-10 and TNF-α . Studies also suggested elevated levels of IL-8, MCP-1, IFNγ, CXCL9, CXCL10 and GM-CSF in COVID-19 patients Marchetti et al., 2018;Conti et al., 2020;Vaninov, 2020) regarding triggering the neuronal manifestations. Systemic inflammation following the leukocyte activation prior to its BBB migrating is another major mechanism toward viral neurological complications (Campbell et al., 2014). The released inflammatory agents change the BBB permeability, triggers the neuroinflammatory flows and drive neuronal hyper-excitability through the activation of glutamate receptors, leading to acute seizure (Libbey et al., 2011;Yavarpour-Bali and Ghasemi-Kasman, 2020). Considering the crucial role of inflammation in the neuropathogenesis of COVID-19, phytochemicals with neuronal anti-inflammatory effects could pave the road in combating related neuronal manifestations. Recent reports also have declared the critical role of phytochemicals in health care through their antiviral (Fitriani et al., 2020) and the inhibition of neuroinflammatoryinterconnected pathways (Abbaszadeh et al., 2020). Phytochemicals with potential antioxidant and antiinflammatory effects (e.g., carotenoids and polyphenols) interact with major transcription factors such as Nrf2 and NF-κB (Iddir et al., 2020). Naringin ( Figure 1) is a phenolic phytochemical belonging to the flavonoid class, possessing anti-neuroinflammatory (Chen et al., 2016;Chtourou et al., 2016;Ngwa et al., 2020), and antiviral (Ng et al., 1996) effects with the potential of being used in the prevention/treatment of COVID-19 (Dabaghian et al., 2020). Naringin also inhibits the expression level of cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS), IL-1β and IL-6 via suppressing high mobility group box 1 (HMGB1) in COVID-19 (Park et al., 2003;Huang et al., 2020a). It also declined the expression level of p38MAPK to inhibit HMGB1 generation of inflammatory mediators and associated lung injury (Gil et al., 2016;Kim et al., 2019b). According to the critical destructive role of inflammatory mediators in the neurological signs of COVID-19, naringin seems to be a hopeful anti-inflammatory/antiviral candidate in combating related neuronal manifestations. As an aglycone form of naringin, naringenin has similarly shown antineuroinflammatory (Nouri et al., 2019;Alberca et al., 2020), and antiviral effects with the potential of being used against COVID-19 (Tutunchi et al., 2020). We have previously shown the neuroprotective potential of naringenin through modulation of inflammatory mediators (NF-κB, TNF-α, IL-1β, etc) and microglia activation in the CNS (Nouri et al., 2019), thereby it could mitigate the neuronal signs of COVID-19 mediated by the inflammatory mediators. As another phenolic compound, resveratrol has shown promising beneficial effects against COVID-19, through the activation of ERK1/2 and SIR1 signaling pathways related to survival, DNA protection Ma and Li, 2020), and anti-neuroinflammatory responses (Bastianetto et al., 2015). It also inhibits neuroapoptosis by reducing FGF-2 and suppressing NF-κB . Considering the critical role of the aforementioned inflammatory mediators in COVID-19 (Yarmohammadi et al., 2020), resveratrol could potentially decline neuroinflammatory signs of COVID-19 patients (Chen et al., 2005). As a major natural derivative of resveratrol, polydatin potentially decline the neural levels of NF-κB, TNFα, IL-1β, IL-6, IL-8, prostaglandin E2 (PGE2), NO, COX-2, iNOS, matrix metalloproteinase (MMP)-3 and MMP-9, thereby could be a novel agents in combating neuronal inflammatory manifestation in COVID-19 (Lo Muzio et al., 2020). A recent study by Bonucci et al., has also introduced polydatin as a protective phytochemical against COVID-19 (Bonucci et al., 2020). So, focusing on their ameliorating effects against neuroinflammation, as well as related antiviral properties, resveratrol and plydatin derivative could be of candidate phytochemicals in combating neuronal signs of COVID-19.
Additionally, several lines of evidence indicated that asiaticoside (a saponin), borneol (a terpene), catalpol (an iridoid) as other phytochemicals declined the neuronal levels of TNF-α, IL-6, TLR4, NF-κB, IL-β and IL-8, thus may be hopeful agents against neurological symptoms in COVID-19 (Welcome, 2020). In fact, since inflammation triggers several cascades of CNS pathogenesis in COVID-19, suppressing related mediators could potentially ameliorate related symptoms. Among other phytochemicals, some alkaloids also show promising antiinflammatory and antiviral effects (Chen et al., 2015;Powers and Setzer, 2016), with the potential of being used against COVID-19 (Bleasel and Peterson, 2020). This effect of alkaloids was also confirmed by a recent in silico study by Garg and Roy. In their study, two alkaloids of sophaline D and thalimonine indicated potential antiviral activities by suppressing main viral proteases (Garg and Roy, 2020) and inflammatory pathways (Varadinova et al., 1996;Pour et al., 2019).
Several other phytochemicals play important roles in the inhibition of SARS-CoV-2 such as sarsasapogenin (a steroidal sapogenin), novobiocin (a coumarin), and alpha terpinyl acetate (a terpenoid) . Previously the neuroprotective effects of such plant-derived secondary metabolites have been reported through inhibiting the inflammatory-interconnected mediators (Abbaszadeh et al., 2020;Fakhri et al., 2020b).
Cannabinoids also possess critical anti-inflammatory roles in viral diseases (Walter and Stella, 2004;Rizzo et al., 2020). These compounds are major constituents of the cannabis plant. The physiological roles of cannabinoids and cannabis are primarily mediated by the cannabinoid receptors (CB1R and CB2R), endocannabinoids, and related metabolic enzymes which are widely distributed throughout the body, especially CNS. The mediators of cannabinoid receptors are being considered as potential targets for numerous disorders, including those correlated with inflammation and autoimmune dysregulation (Rizzo et al., 2020). Prevailing evidence are indicating the pivotal anti-inflammatory and immunoregulatory effects of cannabis-derived cannabinoids, through suppressing cytokines, inhibition of immune cell migration/proliferation (Almogi-Hazan and Or, 2020). Besides, selective cannabinoid agonists present a novel way regarding the treatment of virus-associated neuroinflammation. Considering their growing global acceptance for medicinal uses , cannabinoids seem to be of potential agents against inflammatory cytokine and related mortality in COVID-19 .
Overall, phytochemicals with the potential of modulating the immune system and attributed neuronal cytokine storm could pave the road in combating COVID-19 neuronal complications.

Phytochemicals Inhibit ACE2, and Spike Protein Thereby Neural Manifestations in COVID-19
As previously mentioned, SARS-CoV-2 enters the CNS via the ACE2 or TMPRSS2 receptors (El Tabaa and El Tabaa, 2020; Nemoto et al., 2020). In order to decline SARS-CoV-2 entry to neural cells, ACE2 activity should be declined (Battagello et al., 2020). Spike (S) glycoprotein as the main SARS-CoV-2 structural protein with a critical role in binding to the host cell and protecting the virus against some of the host species antibodies, is another target of phytochemicals (Schoeman and Fielding, 2019).
ACE2 is an enzyme found in the outer membrane of the human cell that acts as a binding site for the S protein. Several studies have shown that there is a strong interaction between ACE2 and S protein. So, blocking ACE2 is also another phytochemical strategy to fight SARS-CoV-2 .
Through the same molecular docking analysis piceatannol also has shown neuroprotective responses Talebi et al., 2020) with the potential of binding to ACE2, thereby playing a critical role in the prevention and treatment of COVID-19 (Wahedi et al., 2020;. The phytochemicals, baicalin, scutellarin, and hesperetin, also bind to ACE2, regarding reducing neurological symptoms in COVID-19 (Cheng et al., 2020a). Several in silico studies showed that the binding energy of hesperidin with the SARS-CoV-2 spike protein, and main proteases are lower than that of ritonavir, lopinavir, and indinavir. It could introduce hesperidin as an effective antiviral agent. Hesperidin also has shown to counteract the cell damaging induced by virus infection, inflammation and free radicals (Bellavite and Donzelli, 2020). Many of other phenolic compounds, including naringenin, hesperetin, hesperidin, and baicalin, showed potential inhibitory effects on ACE2 activity, thereby showed potential effects on COVID-19 and related neural manifestations (Muchtaridi et al., 2020). In another study, stilbene-based compounds especially resveratrol, are promising candidate phytochemicals acting via disrupting spike protein and human ACE2 receptor complex (Wahedi et al., 2020).
EGCG and theaflavin gallate seem to be of promising phytochemicals in targeting spike-protein central channel of SARS-CoV-2 . In a recent study by Kulkarni et al., 2020 some terpenoids such as carvacrol, geraniol, anethole, L-4-terpineol,cinnamyl acetate, thymol and pulegone, and other phenolic as cinnamaldehyde were effective antiviral agents with potential inhibitory effects on viral spike protein. In this line, nimbin (a triterpenoid) and curcumin (polyphenol) showed high binding affinity regarding interacting with ACE2 and the S protein (Maurya et al., 2020). Consistently, Chen and Due estimated the BE of ACE2 interaction with the flavonoid glycoside scutellarin and the triterpenoid glycyrrhizin as a -14.9 and -9 kcal/mol, respectively, that were more strong than other studied phytochemicals including baicalin, hesperetin, and nicotianamine (Chen and Du, 2020). A study by Vardhan et al., showed that one hundred fifty-four analogous of limonoids and triterpenoids showed potential inhibitory effects on ACE2, 3CLpro, PLpro, spike protein, and RdRp. Another in silico study also showed that limonin, obacunone, ursolic acid, glycyrrhizic acid, 7-deacetyl-7-benzoylgedunin, maslinic acid, and corosolic acid effectively target SARS-CoV-2 proteins (Vardhan and Sahoo, 2020).
Evaluated by molecular docking analysis, dithymoquinone (a quinone, Figure 2) showed neuroprotective responses Talebi et al., 2020) through binding to ACE2, to show key roles in the prevention and treatment of COVID-19 (Wahedi et al., 2020;. As a potential phytochemical of Nigella sativa L. (Ranunculaceae), dithymoquinone, with binding affinity of -8.6 kcal/mol, showed a higher potential of binding at SARS-CoV-2 ACE2 . According to the molecular modeling results on SARS-CoV-2, a new indazole alkaloid from the seeds of N. sativa, nigellidine meaningfully bind to active sites of SARS-CoV-2 .
The main phytochemicals with reported inhibitory effects on ACE2 and spike proteins are presented in Table 1.

PHARMACOKINETIC INTERACTION AND BBB PERMEABILITY OF PHYTOCHEMICALS: AN APPROACH TO NOVEL DELIVERY SYSTEMS
However, the neuroprotective effects of such phytochemicals have been provided in several studies, estimations of the permeability through the BBB of the phytochemicals were assessed by the SwissADME program (Daina et al., 2017). Information on the estimations of permeability through the BBB, as well as predict absorption, distribution, metabolism, and excretion (ADME) parameters, pharmacokinetic properties, druglike nature and medicinal chemistry friendliness are shown in Supplementary Table S1. Among the fifty-five phytochemicals, the screening of BBB permeability gave fifteen compounds with a positive effect. Among these are the monoterpenoids 1,8-cineole and carvacrol; the alkaloids 6-acetonyldihydrochelerythrine, allocryptopine, berberine, piperine, protopine, thebaine, and triptanthin; the flavonoid chrysin; the quinones dithymoquinone and tanshinone I; the phenolic compounds resveratrol and cinnamaldehyde; and the lignan savinin. To overcome the aforementioned pharmacokinetic drawbacks of some phytochemicals, novel delivery systems are being applied regarding increasing their penetration to BBB. Accordingly, nano-formulations, polymeric micelles, nano-/microemulsions, nano-gels, solid lipid nano-particles, polymer composites, and liposome/phospholipid have been studied so far (Abbaszadeh et al., 2020;Fakhri et al., 2020a).
As previously mentioned, inflammatory conditions play critical roles during the pathogenesis of COVID-19 disease. It is worth noting that inflammation could increase the BBB penetration of phytochemicals to facilitate their central permeation. This pathophysiological condition simplifies the CNS penetration of those phytochemicals with limitations in their penetration.

DISCUSSION
COVID-19 pandemic is an important threat to human life. Up to now, no effective drug or vaccination has been provided to combat various complications in COVID-19. So, finding therapeutic agents to combat related manifestations in COVID-19, is of great importance. Among different complications of COVID-19 the neurological manifestations have attracted particular attention. Growing evidence is highlighting the involvement of multiple dysregulated mechanisms behind the pathophysiology of COVID-19 neurological manifestations, including hypoxia, neuroinflammation, ACE2/spike proteins, and related enzymes in virus proliferation (e.g., RdRP, 3CLpro, and PLpro). So, providing multi-target agents could pave the road in combating associated neuronal manifestations in COVID-19. For many years, the plant kingdom has shown promising antiviral, and anti-neuroinflammatory results. Accordingly, the hope regarding identifying new applications for the candidate phytochemicals has a successful history in complementary/alternative medicine. We previously showed the antiviral approaches and therapeutic targets of plantderived secondary metabolites in various steps of viruses life cycle, including penetration, uncoating, replication, and release (Pour et al., 2019). In the present study, potential phytochemicals with antiviral effects and modulatory potentials against neuroinflammation, ACE2/spike protein, and related main proteases in the virus life cycle have been highlighted regarding inhibiting the penetration/attachment and replication phases of coronaviruses (Figure 3). Among the aforementioned phytochemicals, in silico/in vitro results introduced polyphenols (mainly flavonoids), alkaloids, and terpenes/terpenoids as potential candidates in counteracting the neurological signs of COVID-19. Although the BBB limits the CNS penetration of some phytochemicals, the disease-related inflammatory conditions as well as novel delivery systems could potentially overcome the BBB dynamic and drawback the limitation. As the results, flavonoids like naringin and it aglycone (naringenin), theaflavins, silymarin, curcumin, EGCG, polyphenol resveratrol and its derivative (polydatin), as well as some phytosterols and cannabinoids showed the most simultaneous anti-neuroinflammatory and antiviral potentials in combating SARS-CoV-2 neural complications. To suppress the viral penetration/attachment the flavonoids hesperidin, chrysin, kaempferol, quercetin, fisetin, baicalin, naringenin, EGCG, and theaflavin as well as some terpenes chalcones, glycyrrhizin, nimbin and alkaloids like berberin, thebaine, piperine as well as terpenoids have shown a more potential future in targeting ACE2/spike proteins. Consequently, regarding targeting the main proteases of coronaviruses flavonoids apigenin, cyaniding, delphinidin, EGCG, theaflavin, naringenin, hesperidin, quercetin and kaempferol, as well as some chalcones, steroidal alkaloid, terpenoids, and quinones are of potential candidates in inhibiting the main proteases of coronaviruses. Overall, the aforementioned phytochemicals have shown growing evidence to be of potential agents in combating neurological signs of COVID-19 through attenuation of neuroinflammation, ACE2/ spike proteins, and main proteases.
Such studies could pave the road regarding finding novel therapeutic agents in combating neurological manifestations in COVID-19. Further reports are required to reveal the precise dysregulated pathways responsible for COVID-19 neurological signs, as well as potential therapeutic phytochemicals.

AUTHOR CONTRIBUTIONS
Conceptualization, SF, MF, and JE; drafting the manuscript, SF, SP, MM; Software: SF, review and editing the paper: SF, MF, and JE; All authors have read, revised and agreed to the published version of the manuscript.