1 Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA, USA
2 Library and Information Access, San Diego State University, San Diego, CA, USA
Submission: December 01, 2018; Published: December 14, 2018
*Corresponding author: Peter Kovacic, Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA, USA
How to cite this article: Peter Kovacic, Wil Weston. Stroke: Unifying Mechanism Involving Antioxidant Therapy, Reactive Oxygen Species, and Oxidative
Stress . Nov Appro Drug Des Dev 2018; 4(4): 555641. DOI: 10.19080/NAPDD.2018.04.555641
Reactive oxygen species (ROS) and oxidative stress (OS) play roles in stroke, as also in Alzheimer’s (AD), Parkinson’s (PD) disease and Schizophrenia (SCZ). Various sources, including oxidases, serve as generators of ROS-OS, such as mitochondria, NADPH, cytochromes P450, monoamines, ET metal complexes, G72 gene, and microglia. Many novel examples of antioxidants (AOs) exert a positive influence on the harmful effects, namely through a unifying mechanism based on ET-ROS-OS-AO. Drugs for treatment of stroke are discussed in relation to the unifying theme including phenolic and phenolic ethers.
Stroke is a leading cause of death and disability  and ischemic stroke is the second leading cause of death worldwide . A stroke is a brain injury that takes place due to disruption of blood supply for various reasons . This event is classified into these categories, hemorrhage (bleeding in diverse parts of the brain, and thrombotic (clot formation in the artery due to
atherosclerosis, the most common type.), embolic (a blood clot or other debris traveling to the brain causing harm). Symptoms, which can occur in different areas of the brain, are as follows: dizziness or confusion, numbness, visual disturbance or loss, difficulty walking, slurred speech, seizures, stupor, coma, and irregular breathing . Stroke may be preceded by transient, ischemic attacks. Risk factors include smoking, diabetes, high blood pressure, heart disease, and genetics.
Stroke fits into the unifying mechanism which has been widely applied, previously in an article involving electron transfer (ET), reactive oxygen species (ROS) and oxidative stress (OS) . This unifying mechanism argues that the preponderance of bioactive substances, usually as the metabolites, incorporate ET functionalities. We believe these ET-metabolites play an important role in physiological responses. The main group includes quinones (or
phenolic precursors), metal complexes (or complexes), aromatic
nitro compounds (or reduced hydroxylamine and nitroso derivatives),
and conjugated imines (or iminium species). Resultant
redox cycling is illustrated in Figure 1. In vivo redox cycling with
oxygen can occur, giving rise to OS through generation of ROS,
such as hydrogen peroxide, hydroperoxides, alkyl peroxides, and
diverse radicals (hydroxyl, alkoxyl, hydroperoxyl, and superoxide)
(Figure 1). Cellular and mitochondrial enzymes can also perform
catalytically in the reduction of O2.
In some cases, ET results in involvement with normal electrical
effects (e.g. neurochemistry). Generally, active entities possessing
ET groups display reduction potentials in the physiologically
responsive range. Hence, ET in vivo can occur resulting in
production of ROS, which can be beneficial in cell signaling at
low concentrations but produce toxic results at high levels.
Electron donors consist of phenols, N-heterocycles or disulfides in
proteins, which produce relatively stable radical cations. ET, ROS
and OS have been increasingly implicated in the mode of action
of drugs and toxins, e.g. anticancer drugs , carcinogens ,
cardiovascular toxins , toxins , ototoxins  and various
other categories .
In addition to the above, there is a plethora of experimental
evidence supporting the theoretical framework. This evidence
includes generation of the common ROS, lipid peroxidation,
degradation products of oxidation, depletion of AOs, effect of
exogenous AOs, and DNA oxidation and cleavage products, as
well as electrochemical data . This comprehensive, unifying
mechanism is consistent with the frequent observation that many
ET substances display a variety of activities (e.g. multiple-drug
properties), as well as toxic effects. It is important to recognize
that mode of action in the biodomain is often involved with many
physiological actions and is multifaceted. In addition to ET-ROSOS
in relation to mechanism, much attention in the literature is
paid to AO action entailing physiological effects.
ROS can be beneficial, but at high levels toxic effects often
predominate. There are various sources for these species .
NAPDH oxidase is an important producer of the ROS in various
organs. The G72 gene increased radical generation in cells.
The gene acts as an activator of oxidase. ROS generated by NO
synthase have been implicated in an array of harmful behaviors.
Mitochondria provide another source of ROS-OS which appears to
contribute to aging. Leakage of electrons occurs in the ET chain
which react with oxygen to produce superoxide, a precursor of
another ROS. Other examples of ROS producers are cytochrome
P450, metal complexes, monoamine oxidase and microglia
There is literature for specific sources of ROS-OS in stroke,
which is rare in brain illness. A study found systemic oxidative
damage to lipids and proteins at baseline in stroke .
Malondialdehyde, an OS marker, concentrations correlated
with stroke severity and was associated with hemorrhage
complications. ROS generated from reperfusion injury could be a
cause of brain injury. Canola oil shortens the life span of strokeprone
rats . The oil reduced the AO activities of SOD, GSH
peroxides and catalase and produced a change in oxidative status.
Tetrahydrocannabinol (THC) increases OS and induces
cerebral mitochondrial dysfunction in cannabis-related stroke
. THC increased H2O2 production and mitochondrial free
radical leaks, a source of ROS. A relevant report on THC can be
found in the recent literature . This stroke article is part of a
series on brain illnesses, including Alzheimer’s disease (AD) ,
Parkinson’s disease (PD) , Structure-activity relationship
(SAR) for AD and PD  Schizophrenia , Depression ,
Multiple Sclerosis and Amyotrophic Lateral Sclerosis ,
Dementia , and Huntington’s disease .
Curcumin (Figure 2) and derivatives of curcumin (Figures
3 & 4) were investigated in experimental stroke . Phenolic
ethers (see Figure 2) can undergo cleavage to phenols. Beneficial
AO action was observed in all cases with the methoxy types being
significantly better. Prior work deals with demethylation to AO
phenolics . Another article reports the neuroprotective effect
of curcumin in a stroke model . There was protection against
ischemia via AO activity and neuronal apoptosis. Other studies of
brain illnesses deal with phenolics and phenolic ethers [16,17].
5-Methoxyindole-2-carboxylic acid (MICA) (Figure 5)
provides neuroprotection against stroke . There was a
decrease in OS in MICA treated rats based on decrease in H2O2 and
lipid peroxidation. The mechanism likely involves AO protection,
attenuation of OS, and maintenance of mitochondrial function. The
mitochondrial aspect is related to another report . Nobiletin
(Figure 6) elicits protection against ischemic stroke . There
are accompanying AO and anti-inflammatory responses.
The neuroprotective effects were studied of an AO mixture,
Twendee X, composed of ingredients, such as cysteine (Figure
7), ascorbic acid (Figure 8), and coenzyme Q10 (Figure 9) .
OS and inflammation are important factors in ischemic stroke.
The neuroprotective effects were demonstrated in AO and
anti-inflammatory pathways . Ginsenoside Rd (Figure 10),
an ingredient in ginseng, can improve stroke outcome .
Ginsenoside Rd also attenuates redox imbalance, along with
enhancing AO activities. There are other examples of polyols
acting as AOs, such as sugars like glucopyranose (Figure 11),
which possess significant AO capacity .
Astaxanthin (Figures 1 & 2), a natural AO carotenoid, reduces
cerebral injury in stroke . Neuroprotection is provided
via suppression of ROS and activation of AO defenses. Recovery
was increased through promotion of AO defenses. There is inhibition
of apoptosis and promotion of neural regeneration. Multiple
mechanisms are involved. A related AO is amphotericin B .
Mitochondria damage appears to be involved in brain
stroke . Diphenyl diselenide (Figures 12 & 13) reduced
mitochondrial damage in a stroke model. The neuroprotective
action may be due to the maintenance of redox balance. The
initial injury is attributed to an increase in ROS. There is a
related article by Mancini, et al. (2014), in which the compound,
diphenyl diselenide was determined to mimic endogenous
antioxidant enzymes or be metabolized by thioredoxin reductase
to form selenol intermediate, which can copy the function of the
antioxidant selenoenzymes .
Risperidone (Figure 14), an antipsychotic drug, displays
neuroprotective effects in ischemic stroke . Significant
protection was observed against neuronal death. The
neuroprotective effect is attributed in part to maintenance of AOs.
Losartan (Figure 15) and amlodipine (Figure 16) were studied
for beneficial effects on stroke prone rats . The two agents
upregulated expression of superoxide dismutase (SOD) and
decreased apoptosis. Amlodipine was more effective in decreasing
apoptosis, which may be related to the AO properties of the agent
in an OS environment.
Nitrones (Figure 17) are potent agents for stroke treatment
based on AO, anti-inflammatory, and neuroprotective properties
. In vitro evaluation of brain blood barrier (BBB) penetration
of select nitrones showed that all of them crossed. Nitrones are
electrochemically analogous to iminium (Figure 18) as noted in
the introduction. Manganese superoxide dismutase (MnSOD) is an
important AO enzyme in the central nervous system . MnSOD
is an important therapeutic agent in ischemic stroke by alleviating
OS and apoptosis Other preventative effects involve AO.
The protein Ubiquilin-1 protects mice from OS and ischemic
stroke . The stroke caused neuronal injury which was
alleviated. The protein incorporates AO features. OS was
appreciably weakened. Evidence points to nicotinamide adenine
dinucleotide phosphate (NADPH) as a major source based on
generation of OS. Neuroprotection could be provided through
stress therapy based on AO action . NADPH oxidase type 4
(NOX4) is a major source of OS in acute stroke . Application of
VAS2870, an inhibitor of the oxidase, was remarkably productive.
NOX4 represents a novel class of drug target for stroke therapy.
The following is a brief collection of summaries of other
articles that speak to AO, ROS, OS in association with stroke. AO and
antiapoptotic approaches have been examined in neuroprotection
of stroke. In 2013, Rodrigo et. al noted that ROS has been implicated
in stroke and suggests novel AO approaches for treatment of
ischemic stroke involving OS and pathophysiology . A 2018
report discusses reactive oxygen species – sensitive NO synthase
inhibitor, an agent for stroke treatment, involving AO/NO donor
. In 2017, a report suggested that AO enzyme therapy would
be useful for ischemic stroke . Transglutaminase, a calcium
dependent enzyme, was also involved as a therapeutic target
for OS and excitotoxicity in stroke . In another study, AO
therapy was used on neurotrophins after stroke . Earlier
stroke research, in 2011, was performed involving AO therapy
and thrombolysis, which suggested that co-administration of AO
drugs could augment the value of thrombolytic therapy . A
study by Yi et. al demonstrated AO protection by mitochondrial
HMG-CoA synthase contributed to healing in stroke prone rats
. In a 2010 study, AO therapy involving vascular targeting was
carried out with stroke patients . Later, in 2012, Brea et al.
found OS markers are linked to vascular recurrence .
A 2013 report deals with the effects of OS on vascular
reactivity of stroke prone rats . A 2010 study reported on
the effects of inflammatory processes on the brain of stroke rats,
finding that they could significantly increase survival through
the AO and anti-inflammatory effects of their treatment .
A receptor reduces ischemic stroke through reduction of OS
inflammation . Reception agonist treatment ameliorates
OS and neuroinflammation in ischemic stroke . Traditional
medicines have also been examined. In a 2016 study, Korean
traditional medicine provided neuroprotection for stroke through
AO/apoptotic pathways . Additionally, green tea prevents OS
in stroke models and may have a beneficial impact on cognitive
function after stroke . A 2016 study found that intervention
with AOs may have protecting effects in severe heat stroke .
In 2011 another study examined the relationship between OS,
autoimmunity, and heart risk in Africans with HIV/AIDS .
They found that these clustered factors along with OS may explain
the high risk of stroke in HIV/AIDS patients.