Oxidative Stress and Nutritional Antioxidants in Neurological Diseases

Introduction

This narrative review aims to provide readers with a brief, yet pinpointed overview as to the therapeutic potential of nutritional antioxidants. Given that oxidative stress has a key involvement in the pathogenesis of many neurological diseases (neurodegenerative, cerebrovascular, or inflammatory), targeting oxidative stress through such components (known to medicine for hundreds, if not thousands of years) may prove efficient. Moreover, this paper should be viewed as an incentive to inspire future research, preclinical and particularly clinical, in this field, so that the usage of such components may one day become a validated treatment with a probable wide spectrum. A step-by-step approach to nutrient intervention in neurological diseases is provided in Figure 1.

Materials and Methods

Comprehensive research has been conducted by consulting the PubMed database for relevant reports published between the inception of the archive and January 2025.

The following keywords have been used by themselves or in various combinations to achieve optimal results: “Parkinson’s disease”, “amyotrophic lateral sclerosis”, ”Alzheimer’s disease”, ”multiple sclerosis”, ”small vessel disease”, ”ischemic stroke”, “hemorrhagic stroke”, “inflammation”, “oxidative stress”, “reactive oxygen species”, “mitochondrial dysfunction”, “apoptosis”, “necrosis”, “excitotoxicity”, “lipid peroxidation”, “vitamin C”, “vitamin E”, “coenzyme Q10”, “black tea”, “green tea”, “taurodeoxycholic acid”, “flavonoids”, “curcumin”, “polyphenol”, “antioxidant”, “Ginkgo biloba”, “mecasin”, “citicoline”, “Artemisia”, “Silybum”, “curcumin”, “melatonin”, “saffron”, “vitamin D3”, “Gastrodia elata”, “lavender oil”.

Case reports, preprints, and standalone abstracts have been excluded. Only papers published in English were included in the selection.

Results and Discussions

Parkinson’s Disease

Parkinson’s disease (PD) is a chronic neurodegenerative disease with a characteristic loss of the dopaminergic neurons in the pars compacta of the substantia nigra [1]. Literature has shown that environmental factors (herbicides, pesticides (such as paraquat), industrial pollutants, neurotoxins (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine or MPTP) and its metabolite (1-methyl-4-phenylpyridinium), as well as genetic factors (mutations of DJ-1, Parkin, PINK1) [2] involved in PD pathogenesis induce oxidative stress (OxSt) in the mitochondria [3], reduce the production of adenosine triphosphate (ATP), facilitate the generation of reactive oxygen species (ROS), and finally lead to the apoptosis of dopaminergic cells [2].

Pathogenesis

OxSt contributes to the degeneration of dopaminergic cells in PD [4]. Also, OxSt is tightly linked to other pathogenic mechanisms involved in PD (mitochondrial dysfunction, excitotoxicity, and inflammation); therefore, it is difficult to ascertain whether it is a primary factor in PD or a consequence of the aforementioned mechanisms [3].

In PD, lipid peroxidation is upregulated, and antioxidant pathways (superoxide dismutase — SOD, catalase, glutathione peroxidase — GPx, ceruloplasmin, vitamin E, vitamin C, copper, zinc, selenium) may be insufficient to protect the cells from pathological oxidation [4]. Increased OxSt in association with diminished antioxidant protectors leads to the loss of neurons in the pars compacta, hence the development of PD [4]. Studies have proven lower levels of vitamin C and E in PD patients versus control groups, launching the hypothesis of increased consumption of these vitamins in PD due to OxSt [4]. Excessive ROS production, mitochondrial transport changes, and increased iron deposition in the pars compacta of the substantia nigra are key pathways in PD pathogenesis [1]. There is a close link between ROS formation and mitochondrial dysfunction [1]. Cellular death in PD is thought to be connected to excessive lipid peroxidation, occurring as a consequence of increased oxidation and expenditure of compensatory mechanisms [1]. ROS have a direct cytotoxic impact, as well as an indirect one by impacting mitochondrial complex I, with higher lipid peroxidation [1]. The reduction of this complex leads to the production of more ROS [1].

In PD, α-synuclein deposition induces an activation of the microglia in the pars compacta, thus activating nicotinamide adenine dinucleotide phosphate oxidase (NADPH-oxidase) [1]. The latter’s consequences are, on the one hand, ROS production in the extracellular compartment afflicting nearby neurons, and on the other hand, redox signaling in the microglia, amplifying the pro-inflammatory response with the induction of chronic inflammation [6].

The presence of excessive OxSt in PD is supported by studies that have proven an increase in carbonyl derivatives [7], in indicators of lipid peroxidation [8], and 8-hydroxy-2′-deoxyguanosine (a marker of nucleic acid damage) [9].

Nutrients

Given the involvement of OxSt in the occurrence of PD and the fact that PD treatment (especially L-dopa) may determine, after a long period of usage, the appearance of free radicals, the administration of multiple antioxidant agents in high dosage along with L-dopa may increase the latter’s efficiency [10,11].

In experimental studies, vitamin E was proven to protect cells from OxSt-related damage in PD and the chronic administration of high doses of vitamin E may be a therapeutic strategy in PD treatment or prevention [3,12]. In other experimental studies, vitamin E diminished the OxSt induced by midbrain iron deposits in PD patients, suggesting it may have neuroprotective effects in these patients [13].

Other observational studies on human subjects suggested that a combined administration of high doses of vitamins E and C may determine a slowed PD progression through their antioxidant effect (14), although their efficacy was not proven in double-blind randomized clinical trials (RCTs) [15].

Taurodeoxycholic acid is an antioxidant agent, decreasing ROS reduction, an effect that has been proven when in vivo PD lab models were used [16].

Coenzyme Q10 has an important antioxidant role in the mitochondria and the lipid membrane, some of its antioxidant effects being mediated by its interaction with α-tocopherol. A phase 2 clinical trial on the efficiency of the antioxidant effect of the coenzyme on early PD patients (i.e., patients who did not require specific therapy) versus placebo showed a decrease in the treated patients’ disability [17].

Black and green tea, due to high polyphenol concentration, exert an antioxidant effect and may have a neuroprotective and neuroregenerative effect in this disease, although clear evidence to support this assertion, derived from clinical research, is scarce [18].

Flavonoids enhance the endogenous activation of antioxidant enzymes, inhibit the peroxidation of lipids, and reduce the production of inflammatory mediators [19]. Due to all these actions, flavonoids exert a favorable effect on dopaminergic neurons and mitigate PD manifestations in laboratory studies [19].

An association between PD and a lack of adherence to the Mediterranean diet suggests a potential neuroprotective effect of this diet, through an undetermined mechanism that may attenuate the OxSt and inflammation, which are both recognized pathogenetic factors in PD [20].

Alzheimer’s disease and small vessel disease

Alzheimer’s disease (AD) is a neurodegenerative affliction characterized by the dysfunction of memory, attention, and other cognitive processes; it is the most common form of dementia [21]. Small vessel disease (SVD) may affect microvasculature systemically or mainly in the brain, the latter constituting a devastating cause of stroke and dementia worldwide [22,23].

Pathogenesis

AD mainly determines a synapse affliction, with the development of senile plaques mainly containing β-amyloid (Aβ). Aβ derives from the proteolysis of the amyloid precursor protein performed mainly by the enzymatic actions of β- and γ-secretase, with an imbalance between production and clearance causing the Aβ buildup [21]. The lesions produced by OxSt in AD are associated with an accumulation of Aβ [11]. Aβ buildup is also a central feature of the cerebral amyloid angiopathy form of SVD, to which AD is intimately connected; some might argue that the two constitute an inseparable spectrum [22]. The other form of SVD, deep perforator arteriolosclerosis, centrally features a blood-brain barrier (BBB) dysfunction, subsequent morphological and functional changes to the vascular wall, as well as myelin impairment [22,23].

Aβ determines the release of ROS by attacking mitochondrial enzymes (particularly cytochrome c oxidase), leading to mitochondrial dysfunction, increasing superoxide radicals, conversion to hydrogen peroxide (H2O2), the release of cytochrome, affecting the production of ATP and cellular apoptosis [21].

OxSt increases with aging and it is an important causal factor in the appearance of AD and other neurodegenerative age-related diseases, such as SVD. Moreover, OxSt is thought to bridge the connection between SVD and AD [24]. It is not yet fully understood how neurochemical factors influence the appearance of age-related cerebral lesions, but more and more data has shown the involvement of biometals (Cu, Fe, Zn) in Aβ accumulation. Copper is a potent mediator for the hydroxyl radical, and the high-affinity link between copper and Aβ (via histidine and tyrosine), as well as between zinc and the amyloid precursor protein and Aβ may contribute to the increased OxSt in AD [11].

Apolipoprotein E is a lipid transport molecule believed to be related to ROS and directly to lipid peroxidation in AD [25]. Carriers of apolipoprotein E4 more often have cerebral amyloid angiopathy [24].

To conclude, the involvement of OxSt in AD pathogenesis is supported by the high concentrations of Cu, Fe, Al, and Hg in the brain parenchyma, a high level of lipid peroxidation and DNA oxidation, as well as a decrease in polyunsaturated fatty acids, in cytochrome c oxidase activity, and energy metabolism [11]. OxSt could become a promising link between AD and SVD; therefore, research focusing on OxSt may decrease the neurological manifestations of both illnesses [24].

Nutrients

In preclinical research, caffeine has been associated with a tendency to lower the Aβ levels in early (familial) AD, because of its antioxidant properties [26]. Studies on cerebral amyloid angiopathy models are lacking.

Curcumin is an antioxidant and anti-inflammatory agent (inhibiting cyclooxygenase and lipoxygenase) that has been shown to reduce carbonyl derivatives, facilitating Aβ disaggregation, with possible beneficial effects in AD in animal studies [26]. Curcumin may also aid endothelial function, which is frequently impaired in SVD, as it has been shown to diminish the risk of stroke in animal models [27].

Vitamin E is a potent antioxidant that prevents oxidizing lesions induced by Aβ in cell cultures; it also delays memory impairment in animal studies on AD [28]. Some RCTs suggested vitamin E, through its antioxidant effects, may delay functional disability in patients with mild to moderate AD [29]. Vitamin E tocotrienols have demonstrated a positive impact on white matter lesions (associated with SVD) in an RCT [30].

Polyphenols (such as anthocyanins from berries, catechins and flavonoids from tea, curcumin from turmeric, and resveratrol from grapes) have an antioxidant effect with possibly associated neuroprotection, observed in preclinical models of AD [26]. Dizziness improved in SVD patients taking polyphenols [31].

The association between AD and a lack of adherence to the Mediterranean diet indicates that the latter may have a neuroprotective effect through an as-of-yet incompletely understood mechanism, potentially including an influence on OxSt and inflammation, both involved in AD pathogenesis [32]. Compliance with a Mediterranean diet lowered the burden of white matter lesions in SVD patients [33].

Due to their antioxidant properties, alkaloids such as groenlandicine, berberine, and palmatine from Coptis chinensis rhizomes may find their use in AD treatment [26]. Berberine promotes endothelial health and has been proven to support proper arterial elasticity in human subjects [34].

Milk thistle (Silybum marianum) diminishes OxSt and memory decline in laboratory studies of AD [35]. Milk thistle extracts also favored proper endothelial function in mice [36].

Ginkgo biloba, through its capacity to purge ROS, may reduce Aβ aggregation in AD, which is suggested by certain in vitro studies [26], but on the other hand, this theory has been contested in the literature [37]. Currently, there is little proof to support the routine use of Ginkgo biloba in AD patients [26]. Ginkgo extract had a beneficial yet limited effect on cognitively impaired mice models of SVD [38].

Melatonin overcomes apoptosis, prevents Aβ from interfering with mitochondrial DNA, diminishes lipid peroxidation, and, in high concentrations, protects from the OxSt induced by Aβ [39]. However, more studies are needed to prove its efficiency in delaying progression in early AD stages or in AD prevention [39]. Melatonin was shown to be a potential BBB integrity protector in cell cultures [40].

Coenzyme Q10 is an antioxidant factor that maintains mitochondrial membrane potential during OxSt, while also protecting neural cells from excessive Aβ deposition in laboratory studies of AD [26]. It also eliminates peroxyl radicals and may prove efficacious in AD [17].

Amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease defined by a loss of central and peripheral motor neurons [41].

Pathogenesis

The pathophysiology of ALS onset is quite complex, probably heterogeneous, and not fully understood [42]. OxSt is a common link between various pathogenetic mechanisms of ALS, contributing to: (a) mitochondrial dysfunction: high ROS levels may augment mutations in mitochondrial DNA, and mutations of the Cu-Zn-SOD1 mitochondrial gene are synchronous with increased OxSt; (b) protein aggregation: OxSt is a contributor to the mechanisms of abnormal aggregation of SOD1; (c) axonal transport: certain fragments of axonal neurofilaments are targeted by OxSt [43].

Environmental or modifiable risk factors may be the source of OxSt, incriminated in ALS pathogenesis: (a) smoking induces lipid peroxidation, DNA damage, and cellular death, smokers having a higher risk of ALS (sporadic form); (b) chemicals used in agriculture (pesticides, organophosphates) are linked to ALS and induce mitochondrial dysfunction and ROS production [44].

It is not clear whether OxSt is the main cause of ALS or if it is a consequence of all the other pathogenetic mechanisms involved, but the existence of SOD1 gene mutation among familial cases suggests OxSt is central to the pathophysiology of genetic forms of ALS, at the very least [43].

OxSt could also interfere with ALS pathophysiology by deteriorating the mitochondria that support presynaptic transportation and, hence, affecting presynaptic mechanisms involved in neurotransmission [45]. ROS and reactive nitrogen species (RNS) alter RNA processing, generating mitochondrial dysfunction that eventually leads to neuronal death [46].

In ALS, indicators of OxSt are increased, such as carbonyl derivatives (in sporadic forms), 3-nitrotyrosine (a marker of oxidative lesions, with a higher expression in sporadic forms as well as familial forms associated with SOD1 mutation), 8-hydroxy-2′-deoxyguanosine (a sign of damaged DNA), 4-hydroxynonenal (showing lipid peroxidation) [43].

Nutrients

Laboratory studies have proven that mecasin (also known as KCHO-1, a herbal extract) diminishes OxSt via the gp91phox and MAPK pathways in ALS patients. Mecasin improved motor function and delayed ALS onset in study models [47].

EGb761, a standardized Gingko biloba extract with antioxidant and neuroprotective effects, could prove useful in treating ALS patients [48].

To prevent OxSt from interfering in ALS pathogenesis, various antioxidant agents have been tested, such as vitamin E and vitamin B complex; however, there were no significant proven benefits [43].

Multiple sclerosis

Multiple sclerosis (MS) is a chronic, inflammatory disease of the central nervous system [49,50], defined by perivenous lymphocytic infiltration and macrophage presence in the cerebral parenchyma [51].

Pathogenesis

MS neuropathology is characterized by focal demyelinating lesions and axonal lesions. Neurodegeneration is induced by inflammation and mitochondrial dysfunction, with ROS production as a common element. ROS promotes transendothelial migration of leukocytes, contributing to axon and oligodendrocyte degeneration [52].

ROS occurs mainly by the activation of macrophages, microglia, and astrocytes and are produced through NADPH-oxidase, myeloperoxidase, and inducible NO-synthase. ROS leads to neuron, axon, myelin, and oligodendrocyte destruction and may contribute to mitochondrial dysfunction, which in turn exacerbates ROS production, augmenting MS lesion appearance [52]. Through lipid, protein, and DNA oxidation, OxSt leads to cellular dysfunction and, finally, to necrosis or apoptosis [53]. In the early stages of MS, OxSt is associated with microglial activation and the inflammatory process, whereas in advanced stages, it is linked to mitochondrial dysfunction, pathological iron accumulation in cerebral structures and its release in demyelinating lesions [54]. Myelin and oligodendrocytes are the most damaged by OxSt in this disease, a phenomenon that has been supported by the cytoplasmic accumulation of oxidated lipids and nuclear DNA alterations [54].

Nutrients

Melatonin presents neuroprotective effects and may decrease the OxSt in individuals with secondary progressive MS [55] by ROS neutralization and induction of antioxidant enzymes [49]. Coenzyme Q10 potentially diminishes OxSt and stimulates the activity of antioxidant enzymes in relapsing-remitting MS [56].

Saffron extract attenuated OxSt in experimental studies on MS [57].

Vitamin D3 has antioxidant properties and has been shown to halt lipid peroxidation in MS literature [58].

Ischemic stroke and intracerebral hemorrhage

Ischemic stroke (IS) is the most widespread type of cerebrovascular affliction and a relevant cause of death and disability worldwide. Intracerebral hemorrhage (ICH) is about 30% of all non-traumatic strokes worldwide, with a higher disability rate compared to IS [59]. The major cause of ICH is small vessel disease, a complex microvascular affliction of the brain [23].

Pathogenesis

Normally, the BBB protects against neurotoxins. After ischemia occurs, various mediators of inflammation, as well as other potentially neurotoxic molecules, cross the altered BBB to the brain parenchyma, contributing to neuronal lesions [60]. A breakdown of the BBB also occurs in ICH, as well as an enhanced proinflammatory response with a release of ROS [61,62].

OxSt is an important factor involved in the pathophysiology of IS [63]. Immediately after a cerebral injury is produced in IS as a result of vascular obstruction, the rapid increase of ROS determines the extension of the ischemic area [64]. OxSt also occurs in ICH and may surprisingly have a disseminated impact, such as the induction of glomerular dysfunction [65].

The brain is particularly sensitive to oxidative lesions. The main sources of ROS in the brain are the mitochondrial respiratory chain, NADPH-oxidase (especially isoforms 2,3,4 that are notably expressed in the central nervous system) and xanthine oxidase (XO). Superoxide (O2−), physiologically produced by the mitochondria, is converted via SOD to H2O2 and acts as a cellular messenger, with a role in neuronal signaling in the central and peripheral nervous system. Oxygen depletion in ischemic neurons favors anaerobic glycolysis, with higher lactate levels and acidosis. The latter contributes to OxSt, providing H+ and hence facilitating O2− conversion to H2O2 [60].

After cerebrovascular flow is reestablished, the mitochondrial respiratory chain is reestablished with the generation of a new peak of ROS [63], contributing to cerebral reperfusion lesions [60]. O2− is involved in reperfusion lesions and NADPH-oxidase contributes to its production [60]. Mitochondrial malfunction has also been detected in ICH around the hematoma [66].

During cerebral ischemia, ATP is broken down to hypoxanthine, which accumulates in the ischemic cerebral parenchyma, and during the reperfusion phase, XO facilitates hypoxanthine oxidation to xanthine and subsequently to uric acid, a process during which O2− and H2O2 are generated [60].

An increase in excitotoxic amino acids such as glutamate in cerebral lesions as well as in the perihematoma region in ICH also favors the production of ROS [63,67].

Excessive ROS leads to lipid peroxidation and a deterioration of proteins and nucleic acids, hence the lesion area is extended and finally, necrosis and apoptosis occur [63]. Lipid peroxidation is the main pathway through which ROS impacts neurons: phospholipase A2 is activated by ROS and subsequently releases arachidonic acid, further enhancing the production of ROS. By impacting lipids, ROS produces aldehydes, dienals, and alkanes, thus provoking neuronal apoptosis. The process of DNA oxidation has an early onset in ischemia, and, although it is initially reversible, then an irreversible deterioration of DNA and cellular death appear due to all the ROS production pathways and a blockage of antioxidant mechanisms [60].

Nutrients

Vitamin C, playing the role of an oxygen donor, can revert oxidative processes [60]. Vitamin E is a lipid antioxidant capable of inhibiting lipid peroxidation and acting as a ROS scavenger [68]. In an experimental study, vitamin C and E administration diminished lipid peroxidation and IS volume [69], but their therapeutic effects were not proven in human observational studies [68,70,71]. Vitamin C plasma levels are reduced in ICH patients [72] and administering vitamin C and E in combination with ICH rat models had positive effects [73].

Coenzyme Q10 is a component of the mitochondrial transport chain, the latter being involved in ROS production [74]. Coenzyme Q10 builds up in the mitochondria, having a powerful antioxidant effect, proving its efficacy in neuronal protection in IS experimental models [75]. Coenzyme Q10 therapeutic strategies in ICH are also under investigation [76].

Citicoline is a natural component that may reduce the release of fatty acids during lipid peroxidation [74]. Citicoline has demonstrated protective effects in experimental IS studies [77], but these results were not obtained in IS patients [78]. Small double-blind trials on citicoline in ICH have shown an increase in muscular strength, however, this needs to be proven in larger studies [79].

Wormwood (Artemisia absinthium), a plant of the Asteraceae family, increases ROS purging and diminishes lipid peroxidation, managing to reduce IS volume in experimental literature [80]. Eupatilin, an Artemisia-derived flavone with antioxidant properties, had neuroprotective effects by reducing inflammation in the microglia in ICH cellular models [81]. Ginkgo biloba extract reduces lipid peroxidation and protects neurons against OxSt in experimental studies [82]. There is no convincing data to support its routine use in IS patients [83]. A systematic review on ginkgo biloba extract in ICH patients has recently shown promise for this therapy, but further validation is needed [84].

Gastrodia elata is a plant belonging to the Orchidaceae family with antioxidant activity, capable of inhibiting glutamate neurotoxicity [85]. In animal studies, it confers neuroprotection against cerebral lesions caused by ischemia and reperfusion [86]. In animal models, lavender oil proved to have antioxidant properties, reducing ROS levels in ischemic or reperfusion lesions [87]. Cannabinoids, mainly cannabidiol, have been associated with neuroprotective effects and the studies with rat cortical neuron cultures exposed to toxic levels of glutamate support a further investigation of these compounds in different pathologies, including ischemic stroke [88,89]. Also, cannabidiol is increasingly investigated in other disorders, including psychiatric illnesses, due to its anxiolytic, antidepressant, and antipsychotic properties, and the benefit of being administered as an adjuvant to current treatment, thus potentially decreasing the rate of treatment resistance [90,91].

Conclusion

To summarize, whereas it may play a variety of roles in the pathogenesis of various neurological diseases, oxidative stress is a worthy target to consider in future therapeutic strategies. Natural nutrients may have beneficial effects that can be impactful, pending more validation in the literature. Vitamin E appears as a versatile option, with potential neuroprotective effects in PD, a possible functional role in AD, and an antioxidant capacity in both ischemic and hemorrhagic stroke, although its clinical role requires further, solid proof. Coenzyme Q10 could also be useful to PD, AD, MS, and stroke patients, with a vast potential awaiting exploration. Ginkgo biloba might also hold promise in AD and stroke, but there is limited evidence to support its routine use, despite clinicians nowadays often adding it to therapeutic regimens. Pending improved technologies to refine and standardize natural extracts, as well as solid and validated methodology usage in RCTs, novel therapies may include nutrients in a plethora of neurological diseases.

Glossary

Aβ = β-amyloid; AD = Alzheimer’s disease; ALS = amyotrophic lateral sclerosis; ATP = adenosine triphosphate; BBB = blood-brain barrier; GPx = glutathione peroxidase; ICH = intracerebral hemorrhage; IS = ischemic stroke; MPTP = 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NADPH = nicotinamide adenine dinucleotide phosphate; OxSt = oxidative stress; PD = Parkinson’s disease; RNS = reactive nitrogen species; ROS = reactive oxygen species; SOD = superoxide dismutase; SVD = small vessel disease; XO = xanthine oxidase.

Conflicts of interest and sources of funding

The authors declare no conflict of interest. No artificial intelligence automatically generated text was inserted in this manuscript, and no image was previously published in another journal or is under consideration of being published elsewhere. This research received no external funding.

Authors’ contribution

Conceptualization I.I.E., M.M.M., S.M.G., D.D.; methodology M.M.M, D.D, R.N., C.I.S., I.I.E; software M.M.M, I.I.E.; validation M.M.M, S.M.G., D.D,; formal analysis M.M, D.D., I.I.E, S.M.G; investigation M.M.M., I.I.E, resources I.I.E., M.M.M.; data curation M.M.M.; writing—original draft preparation, I.I.E., M.M.M., R.N., C.I.S., D.D.; writing—review and editing I.I.E., M.M.M., R.N., C.I.S, D.D.; visualization M.M.M.; supervision M.M.M, D.D., I.I.E; project administration M.M.M, D.D., S.M.G. All authors have read and agreed to the published version of the manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

References

1. Blesa J, Trigo-Damas I, Quiroga-Varela A, Jackson-Lewis VR. Oxidative stress and Parkinson’s disease. Frontiers in Neuroanatomy. 2015;9:91. doi: 10.3389/fnana.2015.00091.
2. Chakraborty S, Bornhorst J, Nguyen TT, Aschner M. Oxidative stress mechanisms underlying Parkinson’s disease-associated neurodegeneration in C. elegans. International Journal of Molecular Sciences. 2013;14(11):23103–28. doi: 10.3390/ijms141123103.
3. Fariss MW, Zhang JG. Vitamin E therapy in Parkinson’s disease. Toxicology. 2003;189(1–2):129–46. doi: 10.1016/s0300-483x(03)00158-6.
4. Nikam S, Nikam P, Ahaley SK, Sontakke A V. Oxidative stress in Parkinson’s disease. Indian Journal of Clinical Biochemistry. 2009;24(241):98–101. doi: 10.1007/s12291-009-0017-y.
5. Schapira AH. Mitochondria in the aetiology and pathogenesis of Parkinson’s disease. The Lancet Neurology. 2008 Jan;7(1):97–109. doi: https://doi.org/10.1016/s1474-4422(07)70327-7.
6. Surace MJ, Block ML. Targeting microglia-mediated neurotoxicity: the potential of NOX2 inhibitors. Cellular and Molecular Life Sciences. 2012;69(14):2409–27. doi: 10.1007/s00018-012-1015-4.
7. Dias V, Junn E, Mouradian MM. The role of oxidative stress in Parkinson’s disease. Journal of Parkinson’s disease. 2013;3(4):461–91. doi: 10.3233/JPD-130230.
8. Cotman CW, Berchtold NC, Christie LA, Huang YC, Tsai NW, Chen HL, et al. Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends in Neurosciences. 2007;30(9):464–72. doi: 10.1016/j.tins.2007.06.011.
9. Bolner A, Micciolo R, Bosello O, Nordera GP. A Panel of Oxidative Stress Markers in Parkinson’s Disease. Clinical Laboratory. 2016;62(1–2):105–12. doi: 10.7754/clin.lab.2015.150538.
10. Prasad KN, Cole WC, Kumar B. Multiple antioxidants in the prevention and treatment of Parkinson’s disease. Journal of the American College of Nutrition. 1999;18(5):413–23. doi: 10.1080/07315724.1999.10718878.
11. Valko M, Leibfritz D, Moncol J, Cronin MTD, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. The International Journal of Biochemistry & Cell Biology. 2007;39(39):44–84. doi: 10.1016/j.biocel.2006.07.001.
12. Zhang SM, Hernán MA, Chen H, Spiegelman D, Willett WC, Ascherio A. Intakes of vitamins E and C, carotenoids, vitamin supplements, and PD risk. Neurology. 2002;59(8):1161–9. doi: 10.1212/01.wnl.0000028688.75881.12.
13. Lan J, Jiang DH. Desferrioxamine and vitamin E protect against iron and MPTP-induced neurodegeneration in mice. Journal of Neural Transmission. 1997;104(4–5):469–81. doi: 10.1007/BF01277665.
14. Roghani M, Behzadi G. Neuroprotective effect of vitamin E on the early model of Parkinson’s disease in rat: behavioral and histochemical evidence. Brain Research. 2001;892(1):211–7. doi: 10.1016/s0006-8993(00)03296-0.
15. Group TPS. Effects of Tocopherol and Deprenyl on the Progression of Disability in Early Parkinson’s Disease. New England Journal of Medicine. 1993;328(3):176–83. doi: 10.1056/NEJM199301213280305.
16. Castro-Caldas M, Carvalho AN, Rodrigues E, Henderson CJ, Wolf CR, Rodrigues CMP, et al. Tauroursodeoxycholic Acid Prevents MPTP-Induced Dopaminergic Cell Death in a Mouse Model of Parkinson’s Disease. Molecular Neurobiology. 2012;46(2):475–86. doi: 10.1007/s12035-012-8295-4.
17. Beal MF. Mitochondrial Dysfunction and Oxidative Damage in Alzheimer’s and Parkinson’s Diseases and Coenzyme Q 10 as a Potential Treatment. Journal of Bioenergetics and Biomembranes (JOBB) Journal of Bioenergetics and Biomembranes. 2004;36(4). doi: 10.1023/B:JOBB.0000041772.74810.92.
18. Caruana M, Vassallo N. Tea Polyphenols in Parkinson’s Disease. Adv Exp Med Biol. 2015;863:117-37. doi: 10.1007/978-3-319-18365-7_6.
19. Magalingam KB, Radhakrishnan AK, Haleagrahara N. Protective Mechanisms of Flavonoids in Parkinson’s Disease. Oxidative Medicine and Cellular Longevity. 2015;2015:1–14. doi: 10.1155/2015/314560.
20. Alcalay RN, Gu Y, Mejia-Santana H, Cote L, Marder KS, Scarmeas N. The association between Mediterranean diet adherence and Parkinson’s disease. Movement disorders : official journal of the Movement Disorder Society. 2012 May;27(6):771–4. doi: 10.1002/mds.24918.
21. Querfurth HW, LaFerla FM. Alzheimer’s disease. N Engl J Med. 2010;362(4):329-44. doi: 10.1056/NEJMra0909142. Erratum in: N Engl J Med. 2011 Feb 10;364(6):588.
22. Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol. 2010;9(7):689-701. doi: 10.1016/S1474-4422(10)70104-6.
23. Wardlaw JM, Smith C, Dichgans M. Small vessel disease: mechanisms and clinical implications. The Lancet Neurology [Internet]. 2019;18(7):684–696. doi: 10.1016/S1474-4422(19)30079-1.
24. Lloret A, Esteve D, Lloret MA, Monllor P, López B, León JL, Cervera-Ferri A. Is Oxidative Stress the Link Between Cerebral Small Vessel Disease, Sleep Disruption, and Oligodendrocyte Dysfunction in the Onset of Alzheimer’s Disease? Front Physiol. 2021;12:708061. doi: 10.3389/fphys.2021.708061.
25. Butterfield DA, Pocernich CB, Drake J. Elevated Glutathione as a Therapeutic Strategy in Alzheimer’s Disease. Drug Development Research. 2002;56(3):428-437. https://doi.org/10.1002/ddr.10095.
26. Feng Y, Wang X. Antioxidant Therapies for Alzheimer’s Disease. Oxidative Medicine and Cellular Longevity. 2012;2012:1–17. https://doi.org/10.1155/2012/472932.
27. Lan C, Chen X, Zhang Y, Wang W, Wang WE, Liu Y, Cai Y, Ren H, Zheng S, Zhou L, Zeng C. Curcumin prevents strokes in stroke-prone spontaneously hypertensive rats by improving vascular endothelial function. BMC Cardiovasc Disord. 2018;18(1):43. doi: 10.1186/s12872-018-0768-6.
28. Grundman M. Vitamin E and Alzheimer disease: the basis for additional clinical trials. American J Clin Nutr. 2000;71(2):630S-636S. doi: 10.1093/ajcn/71.2.630s.
29. Shinohara M, Yamada M. [Vitamin E and Alzheimer’s Disease]. Brain Nerve. 2015;67(12):1509-13. Japanese. doi: 10.11477/mf.1416200330.
30. Gopalan Y, Shuaib IL, Magosso E, Ansari MA, Abu Bakar MR, Wong JW, et al. Clinical investigation of the protective effects of palm vitamin E tocotrienols on brain white matter. Stroke. 2014;45(5):1422–8. doi: 10.1161/STROKEAHA.113.004449.
31. Ulivi L, Maccarrone M, Giannini N, Ferrari E, Caselli MC, Montano V, et al. Oxidative Stress in Cerebral Small Vessel Disease Dizziness Patients, Basally and After Polyphenol Compound Supplementation. Curr Mol Med. 2018;18(3):160–5. doi: 10.2174/1566524018666180720165055.
32. Scarmeas N, Stern Y, Tang MX, Mayeux R, Luchsinger JA. Mediterranean diet and risk for Alzheimer’s disease. Annals of neurology. 2006;59(6):912–21. doi: 10.1002/ana.20854.
33. Gardener H, Scarmeas N, Gu Y, Boden-Albala B, Elkind MSV, Sacco RL, et al. Mediterranean diet and white matter hyperintensity volume in the Northern Manhattan Study. Arch Neurol. 2012;69(2):251–6. doi: 10.1001/archneurol.2011.548.
34. Xu MG, Wang JM, Chen L, Wang Y, Yang Z, Tao J. Berberine-induced mobilization of circulating endothelial progenitor cells improves human small artery elasticity. J Hum Hypertens. 2008;22(6):389–93. doi: 10.1038/sj.jhh.1002311.
35. Lu P, Mamiya T, Lu L, Mouri A, Zou L, Nagai T, et al. Silibinin prevents amyloid β peptide-induced memory impairment and oxidative stress in mice. British Journal of Pharmacology. 2009;157(7):1270–7. doi: 10.1111/j.1476-5381.2009.00295.x.
36. Wen X, Peng Y, Zheng B, Yang S, Han J, Yu F, et al. Silybin induces endothelium-dependent vasodilation via TRPV4 channels in mouse mesenteric arteries. Hypertens Res. 2022;45(12):1954–63. doi: 10.1038/s41440-022-01000-4.
37. Garcia-Alloza M, Borrelli LA, Hyman BT, Bacskai BJ, Gustafson D, Tschanz JT, et al. Antioxidants have a rapid and long-lasting effect on neuritic abnormalities in APP:PS1 mice. Neurobiology of aging. 2010 Dec;31(12):2058–68. doi: 10.1016/j.neurobiolaging.2008.11.006.
38. Jiang S, Ma X, Chen Y, Gu B, Sun N, Xiao H. Effects of ginkgo diterpene lactone on brain inflammation and oxidative stress in rats with cognitive impairment of cerebral small vessel disease. Am J Transl Res. 2021;13(6):6382–90.
39. Srinivasan V, Kaur C, Pandi-Perumal S, Brown GM, Cardinali DP. Melatonin and its agonist ramelteon in Alzheimer’s disease: possible therapeutic value. International Journal of Alzheimer’s Disease. 2010;2011:741974. doi: 10.4061/2011/741974.
40. Qin W, Li J, Zhu R, Gao S, Fan J, Xia M, et al. Melatonin protects blood-brain barrier integrity and permeability by inhibiting matrix metalloproteinase-9 via the NOTCH3/NF-κB pathway. Aging (Albany NY). 2019;11(23):11391–11415. doi: 10.18632/aging.102537.
41. Niedzielska E, Smaga I, Gawlik M, Moniczewski A, Stankowicz P, Pera J, et al. Oxidative Stress in Neurodegenerative Diseases. Molecular Neurobiology. 2016;53(6):4094–125. doi: 10.1007/s12035-015-9337-5.
42. Corcia P, Blasco H, Camu W. Génétique de la sclérose latérale amyotrophique [Genetics of amyotrophic lateral sclerosis]. Presse Med. 2014;43(5):555-62. French. doi: 10.1016/j.lpm.2014.01.012.
43. Barber SC, Mead RJ, Shaw PJ. Oxidative stress in ALS: a mechanism of neurodegeneration and a therapeutic target. Biochim Biophys Acta. 2006;1762(11-12):1051-67. doi: 10.1016/j.bbadis.2006.03.008.
44. D’Amico E, Factor-Litvak P, Santella RM, Mitsumoto H. Clinical perspective on oxidative stress in sporadic amyotrophic lateral sclerosis. Free Radic Biol Med. 2013;65:509-527. doi: 10.1016/j.freeradbiomed.2013.06.029.
45. Pollari E, Goldsteins G, Bart G, Koistinaho J, Giniatullin R. The role of oxidative stress in degeneration of the neuromuscular junction in amyotrophic lateral sclerosis. Front Cell Neurosci. 2014;8:131. doi: 10.3389/fncel.2014.00131.
46. Carrì MT, Valle C, Bozzo F, Cozzolino M. Oxidative stress and mitochondrial damage: importance in non-SOD1 ALS. Front Cell Neurosci. 2015;9:41. doi: 10.3389/fncel.2015.00041.
47. Kook MG, Choi SW, Seo Y, Kim DW, Song BK, Son I, et al. KCHO-1, a novel herbal anti-inflammatory compound, attenuates oxidative stress in an animal model of amyotrophic lateral sclerosis. J Vet Sci. 2017;18(4):487-497. doi: 10.4142/jvs.2017.18.4.487.
48. Ferrante RJ, Klein AM, Dedeoglu A, Beal MF. Therapeutic efficacy of EGb761 (Gingko biloba extract) in a transgenic mouse model of amyotrophic lateral sclerosis. J Mol Neurosci. 2001;17(1):89-96. doi: 10.1385/jmn:17:1:89.
49. Adamczyk B, Adamczyk-Sowa M. New Insights into the Role of Oxidative Stress Mechanisms in the Pathophysiology and Treatment of Multiple Sclerosis. Oxid Med Cell Longev. 2016;2016:1973834. doi: 10.1155/2016/1973834.
50. Lipan CG, Mischianu D, Voda VI, Amza RA, Sirbu CA, Antochi FA, Roceanu AM. Management of urinary dysfunction in patients with multiple sclerosis. Rom J Mil Med 2024;CXXII(3):186-190. https://doi.org/10.55453/rjmm.2024.127.3.2.
51. Ortiz GG, Pacheco-Moisés FP, Torres-Sánchez ED, Sorto-Gómez TE, Mireles-Ramírez M, León-Gil A, et al. Multiple Sclerosis and Its Relationship with Oxidative Stress, Glutathione Redox System, ATPase System, and Membrane Fluidity. In: Trending Topics in Multiple Sclerosis. InTech; 2016. doi: 10.5772/64737.
52. Lee DH, Gold R, Linker RA. Mechanisms of oxidative damage in multiple sclerosis and neurodegenerative diseases: therapeutic modulation via fumaric acid esters. Int J Mol Sci. 2012;13(9):11783-11803. doi: 10.3390/ijms130911783.
53. Gilgun-Sherki Y, Melamed E, Offen D. The role of oxidative stress in the pathogenesis of multiple sclerosis: the need for effective antioxidant therapy. J Neurol. 2004;251(3):261-8. doi: 10.1007/s00415-004-0348-9.
54. Lassmann H, van Horssen J. Oxidative stress and its impact on neurons and glia in multiple sclerosis lesions. Biochim Biophys Acta. 2016;1862(3):506-10. doi: 10.1016/j.bbadis.2015.09.018.
55. Miller E, Walczak A, Majsterek I, Kędziora J. Melatonin reduces oxidative stress in the erythrocytes of multiple sclerosis patients with secondary progressive clinical course. J Neuroimmunol. 2013;257(1-2):97-101. doi: 10.1016/j.jneuroim.2013.02.012.
56. Sanoobar M, Eghtesadi S, Azimi A, Khalili M, Khodadadi B, Jazayeri S, Gohari MR, Aryaeian N. Coenzyme Q10 supplementation ameliorates inflammatory markers in patients with multiple sclerosis: a double blind, placebo, controlled randomized clinical trial. Nutr Neurosci. 2015;18(4):169-76. doi: 10.1179/1476830513Y.0000000106.
57. Ghaffari Sh, Hatami H, Dehghan G. Saffron ethanolic extract attenuates oxidative stress, spatial learning, and memory impairments induced by local injection of ethidium bromide. Res Pharm Sci. 2015;10(3):222-32.
58. Tarbali S, Khezri S. Vitamin D3 attenuates oxidative stress and cognitive deficits in a model of toxic demyelination. Iran J Basic Med Sci. 2016;19(1):80-8.
59. GBD 2019 Stroke Collaborators. Global, regional, and national burden of stroke and its risk factors, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Neurol. 2021;20(10):795-820. doi: 10.1016/S1474-4422(21)00252-0.
60. Shirley R, Ord EN, Work LM. Oxidative Stress and the Use of Antioxidants in Stroke. Antioxidants (Basel). 2014;3(3):472-501. doi: 10.3390/antiox3030472.
61. Askenase MH, Sansing LH. Stages of the Inflammatory Response in Pathology and Tissue Repair after Intracerebral Hemorrhage. Semin Neurol. 2016;36(3):288-97. doi: 10.1055/s-0036-1582132.
62. Jones OA, Mohamed S, Hinz R, Paterson A, Sobowale OA, Dickie BR, Parkes LM, Parry-Jones AR. Neuroinflammation and blood-brain barrier breakdown in acute, clinical intracerebral hemorrhage. J Cereb Blood Flow Metab. 2025 Feb;45(2):233-243. doi: 10.1177/0271678X241274685.
63. Gilgun-Sherki Y, Rosenbaum Z, Melamed E, Offen D. Antioxidant therapy in acute central nervous system injury: current state. Pharmacol Rev. 2002;54(2):271-84. doi: 10.1124/pr.54.2.271.
64. Rodrigo R, Fernández-Gajardo R, Gutiérrez R, Matamala JM, Carrasco R, Miranda-Merchak A, Feuerhake W. Oxidative stress and pathophysiology of ischemic stroke: novel therapeutic opportunities. CNS Neurol Disord Drug Targets. 2013;12(5):698-714. doi: 10.2174/1871527311312050015.
65. Chang CY, Pan PH, Li JR, Ou YC, Liao SL, Chen WY, Kuan YH, Chen CJ. Glycerol Improves Intracerebral Hemorrhagic Brain Injury and Associated Kidney Dysfunction in Rats. Antioxidants (Basel). 2021 Apr 19;10(4):623. doi: 10.3390/antiox10040623.
66. Kim-Han JS, Kopp SJ, Dugan LL, Diringer MN. Perihematomal mitochondrial dysfunction after intracerebral hemorrhage. Stroke. 2006;37(10):2457-62. doi: 10.1161/01.STR.0000240674.99945.4e.
67. Qureshi AI, Ali Z, Suri MF, Shuaib A, Baker G, Todd K, Guterman LR, Hopkins LN. Extracellular glutamate and other amino acids in experimental intracerebral hemorrhage: an in vivo microdialysis study. Crit Care Med. 2003;31(5):1482-9. doi: 10.1097/01.CCM.0000063047.63862.99.
68. Schürks M, Glynn RJ, Rist PM, Tzourio C, Kurth T. Effects of vitamin E on stroke subtypes: meta-analysis of randomised controlled trials. BMJ. 2010;341:c5702. doi: 10.1136/bmj.c5702.
69. Zhang XH, Lei H, Liu AJ, Zou YX, Shen FM, Su DF. Increased oxidative stress is responsible for severer cerebral infarction in stroke-prone spontaneously hypertensive rats. CNS Neurosci Ther. 2011;17(6):590-8. doi: 10.1111/j.1755-5949.2011.00271.x.
70. Cook NR, Albert CM, Gaziano JM, Zaharris E, MacFadyen J, Danielson E, et al. A randomized factorial trial of vitamins C and E and beta carotene in the secondary prevention of cardiovascular events in women: results from the Women’s Antioxidant Cardiovascular Study. Arch Intern Med. 2007;167(15):1610-8. doi: 10.1001/archinte.167.15.1610.
71. Bin Q, Hu X, Cao Y, Gao F. The role of vitamin E (tocopherol) supplementation in the prevention of stroke. A meta-analysis of 13 randomised controlled trials. Thromb Haemost. 2011;105(4):579-85. doi: 10.1160/TH10-11-0729.
72. Polidori MC, Mecocci P, Frei B. Plasma vitamin C levels are decreased and correlated with brain damage in patients with intracranial hemorrhage or head trauma. Stroke. 2001;32(4):898-902. doi: 10.1161/01.str.32.4.898.
73. Peeling J, Yan HJ, Chen SG, Campbell M, Del Bigio MR. Protective effects of free radical inhibitors in intracerebral hemorrhage in rat. Brain Res. 1998;795(1-2):63-70. doi: 10.1016/s0006-8993(98)00253-4.
74. Li W, Yang S. Targeting oxidative stress for the treatment of ischemic stroke: Upstream and downstream therapeutic strategies. Brain Circ. 2016;2(4):153-163. doi: 10.4103/2394-8108.195279.
75. Grieb P, Ryba MS, Sawicki J, Chrapusta SJ. Oral coenzyme Q10 administration prevents the development of ischemic brain lesions in a rabbit model of symptomatic vasospasm. Acta Neuropathol. 1997;94(4):363-8. doi: 10.1007/s004010050720.
76. Rajdev K, Mehan S. Neuroprotective Methodologies of Co-Enzyme Q10 Mediated Brain Hemorrhagic Treatment: Clinical and Pre-Clinical Findings. CNS Neurol Disord Drug Targets. 2019;18(6):446-465. doi: 10.2174/1871527318666190610101144.
77. Bustamante A, Giralt D, Garcia-Bonilla L, Campos M, Rosell A, Montaner J. Citicoline in pre-clinical animal models of stroke: a meta-analysis shows the optimal neuroprotective profile and the missing steps for jumping into a stroke clinical trial. J Neurochem. 2012;123(2):217-25. doi: 10.1111/j.1471-4159.2012.07891.x.
78. Dávalos A, Alvarez-Sabín J, Castillo J, Díez-Tejedor E, Ferro J, Martínez-Vila E, et al.; International Citicoline Trial on acUte Stroke (ICTUS) trial investigators. Citicoline in the treatment of acute ischaemic stroke: an international, randomised, multicentre, placebo-controlled study (ICTUS trial). Lancet. 2012;380(9839):349-57. doi: 10.1016/S0140-6736(12)60813-7.
79. Iranmanesh F, Vakilian A. Efficiency of citicoline in increasing muscular strength of patients with nontraumatic cerebral hemorrhage: a double-blind randomized clinical trial. J Stroke Cerebrovasc Dis. 2008;17(3):153-5. doi: 10.1016/j.jstrokecerebrovasdis.2008.01.006.
80. Bora KS, Sharma A. Neuroprotective effect of Artemisia absinthium L. on focal ischemia and reperfusion-induced cerebral injury. Journal of Ethnopharmacology. 2010;129(3):403–9. doi: 10.1016/j.jep.2010.04.030.
81. Qiao HB, Li J, Lv LJ, Nie BJ, Lu P, Xue F, Zhang ZM. Eupatilin inhibits microglia activation and attenuates brain injury in intracerebral hemorrhage. Exp Ther Med. 2018;16(5):4005-4009. doi: 10.3892/etm.2018.6699.
82. Calapai G, Crupi A, Firenzuoli F, Marciano MC, Squadrito F, Inferrera G, et al. Neuroprotective effects of Ginkgo biloba extract in brain ischemia are mediated by inhibition of nitric oxide synthesis. Life Sci. 2000 20;67(22):2673-83. doi: 10.1016/s0024-3205(00)00858-4.
83. Zeng X, Liu M, Yang Y, Li Y, Asplund K. Ginkgo biloba for acute ischaemic stroke. Cochrane Database Syst Rev. 2005;2005(4):CD003691. doi: 10.1002/14651858.CD003691.pub2.
84. Chen S, Tan S, Hou W, Chen X, Bai L, Zou Y, et al. Efficacy and safety of standardized Ginkgo biloba extract as adjuvant therapy for intracerebral hemorrhage in China: A systematic review and meta-analysis. Heliyon. 2024;10(5):e26861. doi: 10.1016/j.heliyon.2024.e26861.
85. Liu J, Mori A. Antioxidant and free radical scavenging activities of Gastrodia elata Bl. and Uncaria rhynchophylla (Miq.) Jacks. Neuropharmacology. 1992;31(12):1287-98. doi: 10.1016/0028-3908(92)90058-w.
86. Yu SJ, Kim JR, Lee CK, Han JE, Lee JH, Kim HS, et al. Gastrodia elata blume and an active component, p-hydroxybenzyl alcohol reduce focal ischemic brain injury through antioxidant related gene expressions. Biol Pharm Bull. 2005;28(6):1016-20. doi: 10.1248/bpb.28.1016.
87. Wang D, Yuan X, Liu T, Liu L, Hu Y, Wang Z, Zheng Q. Neuroprotective activity of lavender oil on transient focal cerebral ischemia in mice. Molecules. 2012;17(8):9803-17. doi: 10.3390/molecules17089803.
88. Sirbu CA, Manole AM, Vasile TM, Toma GS, Dobrican LR, Virvara DG, Vasiliu O. Cannabinoids- a new therapeutic strategy in neurology. Rom J Mil Med 2022;125(3):349-355. doi: 10.55453/rjmm.2022.125.3.1.
89. Hampson AJ, Grimaldi M, Axelrod J, Wink D. Cannabidiol and (-)Delta9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci U S A. 1998;95(14):8268-73. doi: 10.1073/pnas.95.14.8268.
90. Marinescu I, Vasiliu O, Vasile D. Translational approaches in treatment-resistant depression based on animal model. Rom J Morphol Embryol. 2018;59(3):955-964.
91. García-Gutiérrez MS, Navarrete F, Gasparyan A, Austrich-Olivares A, Sala F, Manzanares J. Cannabidiol: A Potential New Alternative for the Treatment of Anxiety, Depression, and Psychotic Disorders. Biomolecules. 2020;10(11):1575. doi: 10.3390/biom10111575.