Pathologies and Non-Regulation of Free Radicals | Herbal Drugs

This article throws light upon the twelve acute pathologies caused due to non-regulation of free radicals. The pathologies are: 1. Cardiovascular Disease 2. Atherosclerosis 3. Stroke 4. Cancer 5. Diabetes 6. Neurodegenerative Diseases 7. Alzheimer’s Disease 8. Parkinson’s Disease 9. Pulmonary Disease 10. Rheumatoid Arthritis 11. Renal Disease 12. Ocular Disease.

Acute Pathology # 1. Cardiovascular Disease:

Cardiovascular disease (CVD) is of multifactorial etiology associated with a variety of risk factors for its development including hypercholesterolem­ia, hypertension, smoking, diabetes, poor diet, stress and physical inactivity amongst others.

Recently, research data has raised a pas­sionate debate as to whether oxidative stress is a primary or secondary cause of many cardiovas­cular diseases. Evidence support­ing ROS as a culprit of myocardial damage due to ischemia-reperfusion.

There have been reports showing a close cor­relation between the production of ROS and simultaneous consumption of endogenous antioxi­dants. Indirect evidence consistent with this view is the cardio protective effects of free radical scavengers and antioxidant supplements.

In addition, direct genetic manipulations to overexpress or under express genes participating in the antioxidant defense also exhibit profound influence on the outcome of ischemia-reperfusion.

In addition to IR injuries, ROS have also been implicated in many clinical conditions including atherosclero­sis, autoimmune diseases, alcoholic liver disease, and various inflammation related disorders. Ac­cumulated evidence has shown that ROS produc­tion is a key event in reperfusion injury when ox­ygen is reintroduced to ischemic tissues.

Oxygen radicals (O₂⁻) are also produced by the electron transport system of the mitochondria and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. The highly toxic ROS are con­verted to hydrogen peroxide (H₂O₂) by superox­ide dismutase (SOD), and then to H₂O by catalase and/or glutathione oxidase.

However, under ischemic conditions, the endogenous antioxidant system is eroded and the tendency for metal ion assisted conversion of H₂O₂ into the destructive hydroxyl radical (OH^•−) is increased.

Acute Pathology # 2. Atherosclerosis:

Atherosclerosis is a condition that results from the gradual build-up of fatty substances, including cholesterol, on the walls of the arteries. This build-­up, called plaque, reduces the blood flow to the heart, brain and other tissues and can progress to cause a heart attack or stroke. This process is com­monly referred to as hardening of the arteries.

An elevated plasma low-density lipoprotein (LDL) concentration is a primary risk factor for the de­velopment of atherosclerosis and coronary artery disease. Reactive oxygen species generated through lipid peroxidation can oxidatively modi­fy i.e. oxidize the amino acid residues of LDL and this can initiate the atherosclerotic process.

Anti-oxidants thought to be able to inhibit oxidative modification of LDL that leads to the accumula­tion of cholesterol in the atherosclerotic lesion.

Many therapeutic agents have been devel­oped to counteract major risk factors for cardio­vascular disease like hyperlipidemia and hyper­tension. However, no therapy is available to ad­dress the root cause of atherosclerosis.

Recently, two groups have emerged with success in design­ing, developing and taking antioxidant-based anti-atherosclerotic candidates to the level of clini­cal-trials.

Japanese study reported an inverse corre­lation between flavonoid (antioxidant) intake and total plasma cholesterol concentrations, other clin­ical studies, stated that fla­vonoid intakes protect against coronary heart dis­ease.

Acute Pathology # 3. Stroke:

Stroke is the third leading cause of death and the major cause of disability in USA. In the general population, incidence of stroke is 1/1000 individ­uals, however, incidence doubles in individuals who are 80 years of age.

Stroke is defined as an abrupt impairment of brain function resulting from occlusion or rupture of in­tra or extra cranial blood vessels. There are sever­al types of stroke: cerebral thrombosis and cere­bral embolism, also classified as ischaemic stroke and subarachnoid haemorrhage, and intra cere­bral haemorrhage also classified as haemorrhagic stroke.

In atherogenesis, fat-laden cream gradually builds up on the surface of passive artery walls and when the deposit (plaque) grows large enough, it eventually closes off an affected ‘pipe’, prevent­ing blood from reaching its intended tissue; after a while, the blood starved tissue dies.

As a result, when a part of the cardiac muscle succumbs, it leads to heart attack and when it affects the brain, it is called a stroke. Many strokes stem instead from less obstructive plaques that rupture suddenly, triggering the emergence of a blood clot, or thrombus, which blocks blood flow.

Cerebral thrombosis is the most common type of stroke and occurs when a thrombus develops on the wall of a cerebral artery, usually damaged by atherosclerosis. There­fore, therapeutics developed for atherosclerosis, based on imbalance between oxidant and anti­oxidant homeostasis appears to be important in treating stroke provided it reaches the brain-tis­sue sites.

Extensive research generated in the re­cent past has disclosed that free radicals play a major role in the damage caused by hypoxia and reperfusion during cerebral ischaemia, affecting a late stage of the ischaemic process.

These de­velopments also support views that agents that scavenge free radicals or prevent their production may be able to prolong the therapeutic time win­dow. Several antioxidants and free radical scavenging-based therapeutics have been recently launched and are under de­velopment for treatment of stroke.

Acute Pathology # 4. Cancer:

Cancer is emerging as a major problem globally; both in more developed and in less developed countries. The recent world cancer report released by WHO observes that world cancer rates are set to double by 2020. The develop­ment of cancer in humans is a complex process including cellular and molecular changes medi­ated by diverse endogenous and exogenous stim­uli.

It is well established that oxidative DNA dam­age is responsible for cancer development. Cancer in­itiation and promotion are associated with chro­mosomal defects and oncogene activation induced by free radicals.

A common form of damage is the formation of hydroxyled bases of DNA, which are considered an important event in chemical car­cinogenesis.

This adduct for­mation interferes with normal cell growth by caus­ing genetic mutations and altering normal gene transcription. Oxidative DNA damage also pro­duces a multiplicity of modifications in the DNA structure including base and sugar lesions, strand breaks, DNA-protein cross-links and base-free sites.

DNA damage that can contribute to the development of lung cancer and other tumors. The highly significant correlation be­tween consumption of fats and death rates from leukemia and breast, ovary, rectum cancers among elderly people may be a reflection of greater lipid peroxidation.

Carcinogenesis is a multistage disease proc­ess that has been classified into initiation, promo­tion and progression stages; and each stage prob­ably involves both genetic and epigenetic chang­es.

These observations have been substantiated experimentally by external admin­istration of carcinogens. Met­abolic activation of carcinogen is a free-radical-dependent reaction. DNA damage mediated by free radicals plays a critical role in carcinogene­sis.

In biological systems, damaged DNA is re­paired enzymatically and cells regain their nor­mal functions. However, disrepair of DNA dam­age may result in mutations such as base substitu­tion and deletion, leading to carcinogenesis. Sequence specificity of DNA damage plays a key role in the mutagenic proc­ess.

Endogenous DNA damage arises from a vari­ety of intermediates of oxygen reduction and sev­eral free radicals have been reviewed to take part in this process by various mechanisms. These reactive species have dif­ferent redox potentials and redox potentials of these free-radical species may play an important role in sequence-specific DNA damage.

Apart from a variety of free radicals, non-radical oxidant like H₂O₂ also plays an important role in DNA damage. In biological systems, H₂O₂ is generated through spontaneous and/or superox­ide dismutase (SOD) catalysed dismutation of O₂^•.

The O₂^• is produced by one electron reduction of molecular oxygen through reaction with free rad­icals and enzymatic reaction catalysed by xan­thine oxidase. H₂O₂ has emerged as a critical molecule not only for cancer cell proliferation, but also in determining the fate of cancer cells exposed to phenolic phytochemicals. Higher amounts of ROS and H₂O₂ are produced in some cancer cells.

The cumulative production of free radicals and H₂O₂ in human melanoma, neurob­lastoma, colon carcinoma and ovarian carcino­ma cell lines are comparable to that in phorbol ester-stimulated human blood neutrophils.

Since cancer cells constitutively produce high amounts of H₂O₂, the concept of constant oxida­tive stress in cancer originated, which provides possible explanation for some of the abnormal characteristics of cancer cells.

It has also been reviewed that phytochemicals (particularly antioxidant polyphe­nols) mediated inhibition of cancer cell prolifera­tion take place through redox-sensitive mecha­nisms.

Cancer cells, particularly those that are highly persistent or metastatic, require a certain level of oxidative stress to maintain a bal­ance between undergoing either proliferation or apoptosis.

They constitutively generate large but tolerable amounts of H₂O₂ that apparently func­tion as signalling molecules in mitogen-activated protein kinase (MAPK) pathway to constantly ac­tivate redox-sensitive transcription factors and re­sponsive genes that are involved in survival of cancer cells as well as their proliferation.

Antioxidants have also been advocated to impart anticancer activities by several other mech­anisms:

(i) Trapping the ulti­mate carcinogen,

(ii) Blocking the metabolic acti­vation of carcinogens,

(iii) Modulating xenobiotic metabolizing enzymes,

(iv) Scavenging free radi­cals,

(v) Inhibiting generation of free radicals,

(vi) Inhibiting promotion stage of carcinogenesis by inhibiting cell proliferation through blocking lipoxygenase/cyclooxygenase pathway or by lowering ornithine decarboxylase activity, and

(vii) By de­creasing the bioavailability of ultimate carcino­gen, etc.

Acute Pathology # 5. Diabetes:

There is considerable evidence that hyperglycemia results in the generation of ROS, ultimately leading to increased oxidative stress in a variety of tissues. In the absence of an appropriate compensatory response from indigenous antioxidant network, the system becomes overwhelmed (redox imbalance), leading to the activation of stress sensitive intra­cellular signalling pathways.

One major conse­quence of this is the expression of gene products that cause cellular damage and are ultimately responsible for late diabetic complications. Apart from playing a key role in late diabetic compli­cations, activation of it or similar signalling pathways also appears to play a role in mediating insulin resistance and impaired insulin secretion.

The ability of antioxidant/free-radical scavengers to protect against the effects of hyperglycemia and free fatty acids along with clinical benefits following antioxidant therapy supports the causative role of oxidative stress in mediating and/or worsening these abnormalities.

A number of reviews have appeared recently, stressing the role of oxidative stress in pathogenesis of cellular dysfunction leading to cardiovascular, hepatic and other complications of diabetes.

Similarly, supplementation with antioxidants has also been shown to decrease oxidative stress and complications in animal models of diabetes and dia­betic patients. Diabetes-induced defects in the homeostasis and the transport of intracellular calcium have been shown to decrease or recover by treatment of diabetic animals with some antioxidants.

Several studies have demonstrated that antioxidants sup­plementation prevents lipid peroxidation, haemo­globin glycation and inhibition of Na⁺, K⁺– AT- Pase and/or Ca⁺²-ATPase activity caused by hy­perglycemia in various cells.

Multiple activities of phytochemicals present in traditional medicines and their preparations have been reviewed recently. There are several medicinal plants the world over used in traditional medicine, which possess rich antioxidant principles and strong anti­oxidant activities.

It has been argued that major anti-diabetic activities from these plants might orig­inate from their antioxidant principles.

Acute Pathology # 6. Neurodegenerative Diseases:

Oxidative stress has been investigated in neuro­degenerative diseases including Alzheimer’s dis­ease (AD), Parkinson’s disease (PD), multiple scle­rosis, amyotrophic lateral sclerosis, memory loss depression.

A large body of evidence indicates that oxidative stress is in­volved in the pathogenesis of AD and PD. Simul­taneously, increasing number of studies show that nutritional antioxidants can block neuronal death and may have therapeutic properties in animal models of these neurodegenerative diseases.

Acute Pathology # 7. Alzheimer’s Disease:

The risk of acquiring AD is considerable in coun­tries with long life expectancies. In USA alone, the current estimate of 3.6 lakh new cases of AD each year is expected to triple in the next 40 years.

AD is the commonest form of dementia with a prevalence of 0.4% in women and 0.3% in men aged 60-69 years. Estimated prevalence of senile demen­tia in Europe increases with age from 1% in man and women of age 60 years to 44.7% in a popula­tion of 90-95 years age.

Selective sensitivity and susceptibility of neu­rons are the most important characteristics of this disorder. Free radical theory of aging suggests that oxidative damage is a major player in degenera­tion of cells.

The role of oxidative stress in the etiology of AD has long been hypothesized, described and supported by a vari­ety of experimental and clinical studies. This re­search has also promoted interest in assessing anti­oxidants for their possible benefits in modifying the course, reducing the risk, or delaying the on­set of AD.

Recent research reveals that dietary antioxidants may have promising therapeutic po­tential in delaying the onset as well as preventing the aging population with AD and its related com­plications.

Characteristic histopathological alterations in AD are neutristic plaques composed largely of amyloid b-peptides and neuronal aggregates of abnormally phosphorylated cyctoskeletal proteins due to over production of ROS.

Vitamin E has been proposed to impart beneficial effect in this connection by quenching the ROS formed, arid selegiline pro­tects neurons by preventing the formation of ROS and by inhibiting oxidative metabolism of cate­cholamines. These advances provide a sound basis for search, design and development of targeted antioxidants for prevention and treat­ment of AD.

Acute Pathology # 8. Parkinson’s Disease:

PD is a neurological syndrome manifested by any combination of tremble at rest, rigidity, bradykinesia and loss of postural reflexes. Neuropatha-logical hallmark of PD is selective degeneration of dopaminergic neurons in the nigrostriatal sys­tem.

These neurons syn­thesize and release dopamine, and toss of dopaminergic influence on other structures in the basal ganglia leads to classical Parkinsionian symptoms.

Epidemiological studies indicate that a number of factors like exposure to herbicides, in­dustrial chemicals, trace metals, cyanide, organic solvents, carbon monoxide and carbon disulphide may increase the risk of developing PD. Majority of them are known to increase ROS and oxidative stress.

Alterations in pro-antioxidant molecules have also been observed in post-mortem tissues from individuals with PD. Activated microglia’s are thought to contribute to neuronal damage using the release of pro-inflammatory and neurotoxic factors like TNFa, IL-1, RNS, and ROS, etc.

Markers of elevated accumu­lation of NO, ROS, TNFa, IL-1 b, INF-g in substan­tia nigra of PD patients have been demonstrated.

Esposito et al suggested that there are many alternative anti-oxidative ap­proaches that may be considered in prospect of clinical trials, including free radical scavengers, indigenous antioxidant enzyme boosters, iron che­lators and drugs that interfere with oxidative me­tabolism of dopamine in Parkinsonism.

Acute Pathology # 9. Pulmonary Disease:

There is now considerable evidence that inflam­matory lung diseases such as asthma and chronic obstructive pulmonary disease (COPD) are char­acterized by systemic and local chronic inflam­mation and oxidative stress.

Oxidants may play a role in enhancing inflammation through the acti­vation of different kinases and redox transcription factors such as NF-kappa B and AP-1.

Acute Pathology # 10. Rheumatoid Arthritis:

Rheumatoid arthritis is an autoimmune disease characterized by chronic inflammation of the joints and tissue around the joints with infiltration of macrophages and activated T cells.

The pathogenesis of this disease is due to the generation of ROS and RNS at the site of inflammation. Oxidative damage and inflammation in various rheumatic diseases were proved by increased levels of isoprostanes and prostaglandins in serum and synovial fluid com­pared to controls.

Acute Pathology # 11. Renal Disease:

Oxidative stress theater a role in a variety of renal diseases such as glomerulonephritis and tubulo-interstitial nephritis, chronic renal failure, pro­teinuria, uremia. The nephrotoxicity is developed due to certain drugs such as cyclosporine, tacrolimus (FK506), gentamycin, bleomycin, vinblastine which is mainly due to oxidative stress via lipid peroxidation.

Heavy met­als (Cd, Hg, Pb, As) and transition metals (Fe, Cu, Co, Cr)-induced different forms of nephropathy and carcinogenicity are strong free radical induc­ers in the body.

Acute Pathology # 12. Ocular Disease:

Oxidative stress is concerned in age-related mac­ular degeneration and cataracts by altering vari­ous cell types in the eye either photo chemically or non-photo-chemically. Under the action of free radicals, the crystalline proteins in the lens can cross-link and aggregate, leading to the formation of cataracts.

In the retina, long-term exposure to radiation can inhibit mitosis in the retinal pig­ment epithelium and choroid, damage the pho­toreceptor outer segments, and has been associ­ated with lipid peroxidation.