Vitamin D and its Possible Relationship to Neuroprotection in COVID-19: Evidence in the Literature.

Vitamin D is a hormone involved in the regulation of important biological processes such as signal transduction, immune response, metabolic regulation and also in the nervous and vascular systems. To date, coronavirus disease 2019 (COVID-19) infection does not have a specific treatment. However, various drugs have been proposed, including those that attenuate the intense inflammatory response, and recently, the use of vitamin D, in clinical trials, as part of the treatment of COVID-19 has provided promising results. It has been observed in some clinical studies that the use of cholecalciferol (vitamin D3) and its two metabolites the circulating form, calcidiol or calcifediol (25-hydroxycalciferol, 25-(OH)-D), and the active form, calcitriol (1,25-(OH)2-D), in different doses, improve the clinical manifestations, prognosis, and survival of patients infected with COVID-19 probably because of its anti-inflammatory, antiviral and lung-protective action. In relation to the central nervous system (CNS) it has been shown, in clinical studies, that vitamin D is beneficial in some neurological and psychiatric conditions because of its anti-inflammatory and antioxidant properties, modulation of neurotransmitters actions, and regulation of calcium homeostasis between other mechanisms. It has been shown that COVID-19 infection induces CNS complications such as headache, anosmia, ageusia, neuropathy, encephalitis, stroke, thrombosis, cerebral hemorrhages, cytotoxic lesions, and psychiatric conditions and it has been proposed that the use of dietary supplements, as vitamin and minerals, can be adjuvants in this disease. In this review, the evidence of the possible role of vitamin D, and its metabolites, as a protector against the neurological manifestations of COVID-19 was summarized.

Dose-Dependent Behavioral and Antioxidant Effects of Quercetin and Methanolic and Acetonic Extracts from Heterotheca inuloides on Several Rat Tissues following Kainic Acid-Induced Status Epilepticus.

Kainic acid (KA) has been used to study the neurotoxicity induced after status epilepticus (SE) due to activation of excitatory amino acids with neuronal damage. Medicinal plants can protect against damage caused by KA-induced SE; in particular, organic extracts of Heterotheca inuloides and its metabolite quercetin display antioxidant activity and act as hepatoprotective agents. However, it is unknown whether these properties can protect against the hyperexcitability underlying the damage caused by KA-induced SE. Our aim was to study the protective effects (with regard to behavior and antioxidant activity) of administration of natural products methanolic (ME) and acetonic (AE) extracts and quercetin (Q) from H. inuloides at doses of 30 mg/kg (ME30, AE30, and Q30 groups), 100 mg/kg (ME100, AE100, and Q100 groups), and 300 mg/kg (ME300, AE300, and Q300 groups) against damage in brain regions of male Wistar rats treated with KA. We found dose-dependent effects on behavioral and biochemical studies in the all-natural product groups vs. the control group, with decreases in seizure severity (Racine's scale) and increases in seizure latency (p < 0.05 in the ME100, AE100, Q100, and Q300 groups and p < 0.01 in the AE300 and ME300 groups); on lipid peroxidation and carbonylated proteins in all brain tissues (p < 0.0001); and on GPx, GR, CAT, and SOD activities with all the treatments vs. KA (p ≤ 0.001). In addition, there were strong negative correlations between carbonyl levels and latency in the group treated with KA and in the group treated with methanolic extract in the presence of KA (r = -0.9919, p = 0.0084). This evidence suggests that organic extracts and quercetin from H. inuloides exert anticonvulsant effects via direct scavenging of reactive oxygen species (ROS) and modulation of antioxidant enzyme activity.

Status epilepticus: Using antioxidant agents as alternative therapies.

The epileptic state, or status epilepticus (SE), is the most serious situation manifested by individuals with epilepsy, and SE events can lead to neuronal damage. An understanding of the molecular, biochemical and physiopathological mechanisms involved in this type of neurological disease will enable the identification of specific central targets, through which novel agents may act and be useful as SE therapies. Currently, studies have focused on the association between oxidative stress and SE, the most severe epileptic condition. A number of these studies have suggested the use of antioxidant compounds as alternative therapies or adjuvant treatments for the epileptic state.

Anticonvulsant and antioxidant effects of Tilia americana var. mexicana and flavonoids constituents in the pentylenetetrazole-induced seizures.

Tilia genus is commonly used around the world for its central nervous system properties; it is prepared as tea and used as tranquilizing, anticonvulsant, and analgesic. In this study, anticonvulsant activity of the Tilia americana var. mexicana inflorescences and leaves was investigated by evaluating organic and aqueous extracts (100, 300, and 600 mg/kg, i.p.) and some flavonoids in the pentylenetetrazole-induced seizures in mice. Moreover, antioxidant effect of these extracts and flavonoids was examined in an in vitro study by using spectrophotometric technique. Significant activity was observed in the methanol extract from inflorescences. An HPLC analysis of the methanol extract from inflorescences and leaves of Tilia allowed demonstrating the respective presence of some partial responsible flavonoid constituents: quercetin (20.09 ± 1.20 µg/mg and 3.39 ± 0.10 µg/mg), rutin (3.52 ± 0.21 µg/mg and 8.94 ± 0.45 µg/mg), and isoquercitrin (1.74 ± 0.01 µg/mg and 1.24 ± 0.13 µg/mg). In addition, significant but different antioxidant properties were obtained among the flavonoids and the extracts investigated. Our results provide evidence of the anticonvulsant activity of Tilia reinforcing its utility for central nervous system diseases whose mechanism of action might involve partial antioxidant effects due to the presence of flavonoids.

Acetonic and Methanolic Extracts of Heterotheca inuloides, and Quercetin, Decrease CCl(4)-Oxidative Stress in Several Rat Tissues.

The present study was designed to test the hypothesis that the acetonic and methanolic extracts of H. inuloides prevent carbon tetrachloride-(CCl(4)) induced oxidative stress in vital tissues. Pretreatment with both H. inuloides extracts or quercetin attenuated the increase in serum activity of alkaline phosphatase (ALP), total bilirubin (BB), creatinine (CRE), and creatine kinase (CK), and impeded the decrease of γ-globulin (γ-GLOB) and albumin (ALB) observed in CCl(4)-induced tissue injury. The protective effect was confirmed by histological analysis with hematoxylin-eosin and periodic acid/Schiff's reagent. Level of lipid peroxidation was higher in the organs of rats exposed to CCl(4) than in those of the animals treated with Heterohteca extracts or quercetin, and these showed levels similar to the untreated group. Pretreatment of animals with either of the extracts or quercetin also prevented the increase of 4-hydroxynonenal and 3-nitrotyrosine. Pretreatment with the plant extracts or quercetin attenuated CCl(4) toxic effects on the activity of several antioxidant enzymes. The present results strongly suggest that the chemopreventive effect of the extracts used and quercetin, against CCl(4) toxicity, is associated with their antioxidant properties and corroborated previous results obtained in liver tissue.

Hepatoprotective effect of acetonic and methanolic extracts of Heterotheca inuloides against CCl(4)-induced toxicity in rats.

A model of hepatotoxicity by carbon tetrachloride (CCl(4)) in rats was used in order to evaluate the protective potential of the acetonic and methanolic extracts of Heterotheca inuloides. Pretreatment with the two H. inuloides extracts attenuated the increase in the activity of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) observed in CCl(4)-induced liver injury. The protective effect was confirmed by the analysis of tissue slides stained with hematoxylin-eosin and periodic acid/Schiff's reagent. Additionally, the two extracts are scavengers to the superoxide radical as was observed by electron paramagnetic resonance. Due to the fact that the methanolic extract resulted in a better protective effect in the previous experiments, it was used to investigate in more detail the mechanism of hepatoprotection. Quercetin, one of the main components of the extract, with known hepatoprotective and antioxidant activity was used as a positive control. Pretreatment of animals with the methanolic extract or quercetin, was associated with the prevention of 4-hydroxynonenal and 3-nitrotyrosine increase in the liver, two markers of oxidative stress. Furthermore, the decrease in the activity of several antioxidant enzymes including superoxide dismutase, catalase and glutathione peroxidase in CCl(4)-induced liver injury was alleviated by the pretreatment with H. inuloides methanolic extract or quercetin. These results suggest that the hepatoprotective capacity of H. inuloides methanolic extract is associated with its antioxidant properties, which would also explain the biomedical properties attributed to this plant.

Antioxidant activity of Heterotheca inuloides extracts and of some of its metabolites.

Arnica (Heterotheca inuloides) is a widely used medicinal plant in México; it has been recognized as anti-inflammatory, analgesic, cytotoxic, scavenger of superoxide anion and also as a preventive of lipid peroxidation. In vivo studies have demonstrated a hepatoprotective action of the methanolic extract of this plant as well as of quercetin, one of its main components, and the evidence obtained pointed out to an antioxidant mechanism. In this work, we focused on the free radical scavenging capacity of acetonic and methanolic extracts of H. inuloides in comparison with reference compounds. The two extracts were 2-12 times more effective (IC50, microg/mL) than the reference compounds to cope with the following radicals or molecules tested: 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS(+)), 2,2-diphenyl-1-picrylhydrazyl (DPPH), peroxynitrite (ONOO(-)), superoxide (O2(-)), singlet oxygen ((1)O(2)), hypochlorous acid (HOCl), hydrogen peroxide (H2O2), hydroxyl (OH). Additionally, five secondary metabolites isolated from the methanolic extract displayed potent concentration-dependent antioxidant effects against reactive oxygen species produced in vitro (IC50 values in the range of 0.018-4.31mg/mL). d-Chiro-inositol showed the higher antioxidant effect against O2(-), H2O2 and OH while spinasterol and quercetin were the most active against (1)O(2) and ONOO(-), respectively. The antioxidant properties of the extracts and metabolites tested partially support the wide use of this plant in traditional medicine.

The effect of nordihydroguaiaretic acid on iodoacetate-induced toxicity in cultured neurons.

Nordihydroguaiaretic acid (NDGA) is present in high concentrations in the desert shrub Creosote bush, Larrea tridentate. This plant has been used in traditional medicine because of its beneficial effects related, at least in part, to its antioxidant properties. Taking into account some evidence about neuroprotective effects elicited by NDGA, we evaluated the effect of this compound on the neurotoxicity induced by iodoacetate (IAA), an inhibitor of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), on cerebellar granule neurons. In addition, as reactive oxygen species play an important role in IAA-induced cytotoxicity, we also studied the enzymatic antioxidant system in IAA-treated cells. We found that IAA caused a dose-dependent decrease in cell viability of cultured neurons with an IC(50) of 18.4 microM and induced increased activity of catalase, glutathione peroxidase, and glutathione-S-transferase. Moreover, NDGA attenuated the toxicity induced by 18.4, 25, and 30 microM of IAA without abolishing the inhibitory effect of IAA on GAPDH activity. Furthermore, NDGA could prevent the inhibitory effect of IAA on aconitase activity, a marker of oxidative stress, suggesting that the protective effect of NDGA on IAA neurotoxicity was associated with the prevention of oxidative stress.

Medicinal properties of mangosteen (Garcinia mangostana).

Many tropical plants have interesting biological activities with potential therapeutic applications. Garcinia mangostana Linn. (GML) belongs to the family of Guttiferae and is named "the queen of fruits". It is cultivated in the tropical rainforest of some Southeast Asian nations like Indonesia, Malaysia, Sri Lanka, Philippines, and Thailand. People in these countries have used the pericarp (peel, rind, hull or ripe) of GML as a traditional medicine for the treatment of abdominal pain, diarrhea, dysentery, infected wound, suppuration, and chronic ulcer. Experimental studies have demonstrated that extracts of GML have antioxidant, antitumoral, antiallergic, anti-inflammatory, antibacterial, and antiviral activities. The pericarp of GML is a source of xanthones and other bioactive substances. Prenylated xanthones isolated from GML have been extensively studied; some members of these compounds possess antioxidant, antitumoral, antiallergic, anti-inflammatory, antibacterial, antifungal and antiviral properties. Xanthones have been isolated from pericarp, whole fruit, heartwood, and leaves. The most studied xanthones are alpha-, beta-, and gamma-mangostins, garcinone E, 8-deoxygartanin, and gartanin. The aim of this review is to summarize findings of beneficial properties of GML's extracts and xanthones isolated from this plant so far.