Mini-Reviews in Organic Chemistry - Volume 10, Issue 4, 2013

Drug addiction is a public health and social burden. Presently, the most abused illicit substance is cannabis, followed by amphetamines, cocaine and opioids, with different prevalence in different countries. Several evidences support a role for oxidative stress in the toxicity induced by many drugs of abuse in different organs, such as the brain, heart, liver or kidneys. This leads to oxidation of important cellular macromolecules, and may culminate in cell dysfunction and death. In this review we describe the evidences for oxidative damage and depletion of antioxidants upon exposure to drugs of abuse, especially amphetamines, cocaine and opiates. We also discuss the sources of oxidative stress induced by drugs of abuse, including oxidative metabolism of drugs, oxidative metabolism of monoamines by monoamine oxidases or by auto-oxidation, mitochondrial dysfunction, excitotoxicity, microglial activation, inflammation, hyperthermia and the effects of drug interactions. These consolidate oxidative stress as a relevant mechanism contributing for the cytotoxicity of drugs of abuse and for behavioral changes associated with drug addiction.

Several studies have attempted to clarify molecular pathways leading to drug addiction. Increased reactive oxygen species production in the central nervous system has been recently proposed to play a pivotal role in the neuropathology induced by drug abuse. In this review, we summarize current knowledge on the involvement of oxidative stress in the development of neural dysfunctions induced by prolonged exposure to specific drugs of abuse: N-methyl-D-aspartate receptor antagonists (ketamine, phencyclidine and dizocilpine maleate), cocaine, heroin, marijuana, gammahydroxybutyrate, amphetamine and methamphetamine. Understanding the role of increased oxidative damage in the central nervous system following abuse of these compounds may provide original molecular perspectives leading to innovative therapeutic strategies.

Oxidative Stress, deriving from a perturbation of the cellular balance between pro-oxidant and anti-oxidant molecules, has been involved in the patho-physiology of multiple diseases, and anti-oxidant supplementation are largely studied for therapeutic purposes. The Cannabis sativa derivates, the cannabinoids (CBs), are widely used as a recreational drug, but pharmacological activities also prompt to therapeutic use. Exposure to CBs rises physical and psychic effects which can evolve in both short-term and long-term toxicity. High inter-individual variation exists in the susceptibility to these effects. Many evidences show a complex modulator action of CBs on cellular oxidative stress, with different outcomes according to cellular type, microenvironment, time and dose of exposition. The subtle balance between anti-oxidant or pro-oxidant action of CBs should be taken into account to achieve a more accurate comprehension of the molecular mechanisms involved in toxicity, considering that OS is not merely a damaging factor, but is also involved in protective pathways.

Methamphetamine and 3, 4-methylenedioxymethamphetamine are psychoactive recreational hallucinogenic substances with considerable CNS stimulatory effects. Acute or sub-chronic exposure to METH or MDMA can damage several organs. Many different organs may be involve. There is evidence for neurotoxicity, cardiotoxicity, hepatotoxicity and nephrotoxicity. Many of these mechanisms are complex and difficult to explain. There is emerging consensus that oxidative stress play a paramount role in the molecular toxicity of both METH and MDMA. Free radicals can arise secondary to oxidative deamination of monoamines, cathecolamines autoxidation, hypothermia, lipoperoxidation and even cellular death. There is very little doubt that the toxic effects of METH and MDMA are mediated either by the direct effect of METH and MDMA or by its redox active metabolites. Metabolites formed in liver cells can reach the others organs (heart, kidney, brain, etc) and produce their own toxic effects inducing cellular oxidative stress and lipoperoxidation. The present review is aimed to further clarify the mechanisms of METH and MDMA-induced toxicity, mainly focusing on the role of oxidative stress pathway.

Opiates are the most effective treatment for acute and chronic severe pain. However, for the fact that they provoke the development of analgesic tolerance as observed in human studies, their clinical utility is often lower. Morphine is a principal opiate, but to get an equivalent pain relief with it, the doses of administration need to be constantly increasing. However, such dose increase has a therapeutic impact by on setting morphine-induced hypersensitivity. This complex pathophysiological cycle contributes significantly to decreased quality of life in the population of subjects with chronic pain. In any case, interests in new approaches that would maintain opiate efficacy during repetitive dosing without engendering tolerance or unacceptable side-effects are growing. Recent evidence has implicated oxidative stress in the development of pain in several pathologies and most importantly in opiate antinociceptive tolerance, caused by the presence of free radicals. This mini-review on some opioids and their possible mechanisms has dual objective: to discuss the importance and role of free radicals in maintenance of pain and induction of opiate antinociceptive tolerance; and to demonstrate that opiates are rational target for therapeutic intervention in pain management, as well as to provide a pharmacological basis for developing inhibitors of free radical biosynthesis.

Morphine exhibits important pharmacological effects for which it has been used in medical practice for quite a long time. However, it has a high addictive potential and can be abused. Long-term use of this drug can be connected with some pathological consequences including neurotoxicity and neuronal dysfunction, hepatotoxicity, kidney dysfunction, oxidative stress and apoptosis. Therefore, most studies examining the impact of morphine have been aimed at determining the effects induced by chronic morphine exposure in the brain, liver, cardiovascular system and macrophages. It appears that different tissues may respond to morphine diversely and are distinctly susceptible to oxidative stress and subsequent oxidative damage of biomolecules. Importantly, production of reactive oxygen/nitrogen species induced by morphine, which have been observed under different experimental conditions, can contribute to some pathological processes, degenerative diseases and organ dysfunctions occurring in morphine abusers or morphine-treated patients. This review attempts to provide insights into the possible relationship between morphine actions and oxidative stress.

Cocaine is one of the principal drugs of abuse, it is an illegal psychostimulant, and the chronic consumption of cocaine causes damage in a range of body organs. Cocaine is known to undergo metabolism through multiple enzymatic pathways leading to the formation of several highly reactive species, which have been proposed to exert a direct toxic effect in the organs. All its metabolites may be involved in the activation of redox cycles, the depletion or decrease of antioxidant enzymes and the consequent generation of reactive oxygen species (ROS) leading to oxidative stress (OS) events, the lipid peroxidation and disruption of cellular activity, and consequently cocaine-induced organs damage. However, the exact mechanisms of cocaine-mediated toxicity in all the organs are not fully understood. This review provides extensive evidence in support of the hypothesis that oxidative metabolites play important roles comprising oxidative stress, defined as a disturbance of redox signaling and control that can cause malfunction in organs such as the brain, heart, liver, kidney and skin.

Alcohol consumption and tobacco smoking are the most common co-abused drugs in the world. They are not only deleterious by themselves to the health of individuals, but they also act synergistically in worsening several disease conditions. Numerous studies have shown that cancer of various organs such as liver and lungs, as well as many disease conditions such as cardiovascular and neurodegenerative involve both alcohol and smoking individually, and together they pose the major risk factors. Similarly, several recent reports have shown that alcohol and smoking are involved in worsening HIV-related conditions. Although some other minor pathways are involved in alcohol- and tobacco-mediated cancers and organ toxicities, cytochrome P450 (CYP) systems are the major pathways that induce reactive oxygen species and toxic metabolites leading to oxidative stress. For example, CYP2E1 is involved in alcohol-mediated oxidative stress leading to liver injury and cancers in many organs. Similarly, CYP2A6 is mainly involved in tobacco-mediated lung cancer, as well as toxicities in other organs including the brain. Therefore, in this review we have discussed the involvement of different isozymes of CYP in alcohol- and smoking-mediated oxidative stress and organ toxicities. In general, we cover 1) prevalence, disease, and life style among alcoholics and smokers, 2) general mechanisms of alcohol- and tobaccomediated oxidative stress, 3) The role of oxidative stress mediated toxicity in different disease states, and 4) clinical implications.

The aim of this review is to discuss the evidence on the potential role of oxidative stress in the mechanisms of AAS-induced toxicity. The adverse effects of chronic consumption of supraphysiological doses of AAS include endocrine, behavioral, hepatic, renal and cardiovascular abnormalities; this is of considerable importance because of the wellknown AAS abuse by adolescent bodybuilders and athletes and the emergence of adverse side effects including a number of cardiac and cardiovascular complications leading eventually to death in some cases. Accumulating evidence indicate that abuse of AAS may cause cardiovascular adverse side-effects including elevated blood pressure, alteration of the structure of the heart, congestive heart failure, stroke, sudden cardiac death and endothelial dysfunction. Under normal physiological conditions a major source of ROS in liver is mitochondria, additional sources in generating ROS are peroxisomes, xanthine oxidase, NADPH oxidase, acyl-CoA oxidase and cytochrome P-450. Poor information are available on the effects of AAS treatment on hepatic antioxidant capacity. Evidence of side effects affecting kidney and the renal function are sporadically emerging from clinical reports of renal disorders among AASs users, especially with elevated and prolonged use. Experimental evidence suggests that both nandrolone administration and strenuous exercise increase the extent of renal damage in response to renal toxic injury. From the data presented, we can realize that to date considerable research has led to the identification of a growing number of AAS-adverse effects due to abuse of these substances.

Linus Pauling has assumed that certain molecules such as functional monomers make self-organized structures around another particle called a molecular template or stamp. Although this theory has proved to be wrong in terms suggested by Pauling, it became the basis for the synthesis of entirely new materials named molecularly imprinted polymers (MIPs) which entered with great dynamics in the world of science in the early 90s of the last century and gradually gaining more and more popularity. These materials are created by using molecular imprinting techniques, providing selective binding property of the spaces within the polymer molecule of a substance used as a “molecular stamp”. The versatility of the process of synthesizing certain molecules on these materials (which can be drugs, pesticides, carbohydrates, nucleotides, proteins) according to simple modification properties obtained a matrix, by selecting the appropriate functional monomer and process conditions. These fillers provide very selective recognition and differentiation of the enantiomers which are particularly useful in medicinal chemistry. For that reason, they find application in almost every area of life, where the chemical analysis is required. MIPs, due to their compatibility to highly complex matrices, are often used for pharmaceutical and biological estimations. In environmental analysis, MIPs are utilized to detect trace amounts of substances, while used in bromatological and toxicological studies as a useful tool in monitoring norms of dangerous and undesirable chemicals. Hence, the article is a review of the current considerations on the preparation and application of MIPs as well as molecularly imprinted membranes (MIM).

Our research group has published numerous papers over the last three years on the reaction of nitrile oxides and azomethine ylide with unsaturated tricyclic N-substituted dicarboximides selected according to the importance of possible biological activities. These reactions cover full range of mechanistic pathways and timings of bond-forming processes to give five-membered ring closure by 1,3-dipolar cycloaddition.