Current Pharmaceutical Design - Volume 10, Issue 6, 2004

The cyclooxygenase isoenzymes, COX-1 and COX-2, catalyze the formation of prostaglandins, thromboxane, and levuloglandins. The prostaglandins are autocoid mediators that affect virtually all known physiological and pathological processes via their reversible interaction with G-protein coupled membrane receptors. The levuloglandins are a newer class of products that appear to act via irreversible, covalent attachment to numerous proteins. COX enzymes are clinically important because they are inhibited by aspirin and numerous other non-steroidal anti-inflammatory drugs. This inhibition of COX confers relief from inflammatory, pyretic, thrombotic, neurodegenerative and oncological maladies. About one hundred years have elapsed since Hoffman designed and synthesized acetylsalicylic (aspirin) as an agent intended to lessen the gastrointestinal irritation of salicylates while maintaining their efficacy. During the past forty years systematic advances in our understanding of the structure, regulation and function of COX isoenzymes have enabled the design and synthesis of COX-2 selective inhibitors as agents intended to lessen the gastrointestinal irritation of aspirin and non-selective NSAIDs. This review discusses: 1) how two separate catalytic processes in COX - peroxidase and prostaglandin synthase - act in an integrated fashion manner to generate prostaglandins; 2) why irreversible inactivation of COX is important constitutively and pharmacologically; 3) how cells have managed to use two closely related, almost identical enzymes in ways that discriminate their physiological versus pathological roles; 4) how investigators have used these advances to formulate and test medically important uses for old drugs (i.e. aspirin) and create new ones that still seek to achieve Hoffman's original goal.

Novel coxibs (i.e. etoricoxib, valdecoxib, parecoxib and lumiracoxib) with enhanced biochemical cyclooxygenase (COX)-2 selectivity over that of rofecoxib and celecoxib have been recently developed. They have the potential advantage to spare COX-1 activity, thus reducing gastrointestinal toxicity, even when administered at high doses to improve efficacy. They are characterized by different pharmacodynamic and pharmacokinetics features. The higher biochemical selectivity of valdecoxib than celecoxib, evidenced in vitro, may be clinically relevant leading to an improved gastrointestinal safety. Interestingly, parecoxib, a pro-drug of valdecoxib, is the only injectable coxib. Etoricoxib shows only a slightly improved COX-2 selectivity than rofecoxib, a highly selective COX-2 inhibitor that has been reported to halve the incidence of serious gastrointestinal toxicity compared to nonselective nonsteroidal antiinflammatory drugs (NSAIDs). Lumiracoxib, the most selective COX-2 inhibitor in vitro, is the only acidic coxib. The hypothesis that this chemical property may lead to an increased and persistent drug accumulation in inflammatory sites and consequently to an improved clinical efficacy, however, remains to be verified. Several randomized clinical studies suggest that the novel coxibs have comparable efficacy to nonselective NSAIDs in the treatment of osteoarthritis, rheumatoid arthritis and acute pain, but they share similar renal side-effects. The apparent dose-dependence of renal toxicity may limit the use of higher doses of the novel coxibs for improved efficacy. Large-size randomized clinical trials are ongoing to define the gastrointestinal and cardiovascular safety of the novel coxibs.

A group of chemical mediators, the eicosanoids, is critical players in a multitude of physiological processes. Generated by the action of the cyclooxygenase (COX) enzyme on arachidonic acid they are responsible for diverse and often opposing actions such as platelet function, vasomotor tone, gastric cytoprotection and inflammation. Since their discovery several decades ago, our knowledge concerning their synthesis, function as natural ligands and methods to manipulate their activity through drug development has expanded. Traditional Non Steroidal Anti-Inflammatory Drugs (NSAIDs) are nonselective inhibitors of the COX enzyme, of which two isoforms are known to exist - COX-1 and COX-2. NSAIDs have been the mainstay of treatment in the management of pain and inflammation associated with acute and chronic inflammatory conditions that affect more than 10 million Americans. Their efficacy in this regard is not questioned. However, gastrointestinal toxicity arising from chronic NSAID ingestion is common and limits their use in clinical practice. Gastrointestinal toxicity has been attributed to the blockade of the COX-1 mediated generation of the cytoprotective prostanoids, such as PGE2 and PGI2. Selective COX-2 inhibitors were designed to inhibit the production of COX-2 dependent inflammatory prostanoids and to leave intact the cytoprotective COX-1 products. The first of a new class of these selective COX-2 inhibitors - the coxibs- were introduced to the market in 1999. These compounds, while exhibiting similar efficacy to traditional NSAIDs, were associated with a reduced incidence of surrogate or actual indices of GI toxicity. Questions have been raised concerning the cardiovascular and renal profiles of these agents based on data from both small and large clinical studies. More recently, our increasing understanding of the relative contributions of both isoforms of the COX enzyme to individual components of vascular homeostais has allowed us to appreciate the cardiovascular and renovascular implications of selective COX-2 inhibition.

Our initial studies on renal cyclooxygenase (COX)-2 expression and activity addressed the critical role of angiotensin II (Ang II) in increasing tumor necrosis factor alpha (TNF) that eventuated in expression of COX-2 in the medullary thick ascending limb (mTAL) of the nephron. COX-2 supplanted the dominant oxygenase, the cytochrome P450 (CYP) enzyme, w- hydroxylase, that synthesized 20-hydroxyeicosatetraenoic acid (20-HETE). These findings served as the basis for additional studies on: 1) the role of glucocorticoids in regulating COX-2 expression and activity in the mTAL; and 2) the utilization of the same signaling pathways in response to stimulation of the mTAL calcium receptor (CaR). These studies of mTAL COX-2 expression which are addressed in the first part of this chapter are followed by explorations of the expression of COX-2 in preglomerular microvessels (PGMV) and the relationship of COX-2 to 20- HETE, the principal eicosanoid of PGMV. The third and last component of this chapter explores the signaling events, focusing on COX-2, which are set in motion by diabetes.

Prior to the discovery of cyclooxygenase-2 (COX-2), a beneficial association was shown between chronic usage of non steroidal anti-inflammatory drugs (NSAIDs), that nonselectively inhibit both cyclooxygenase-1 (COX-1) and COX-2, and prevention of colorectal cancer. The cloning of COX-2 allowed the development of enzyme inhibitors that selectively inhibit COX-2 and also facilitated the expression profiling of COX-2 in many cancer tissues. COX-2 selective inhibitors have shown efficacy in vitro and in vivo in several animal cancer models and in limited human clinical trials. The potency of COX-2 inhibitors in vivo can be attributed to the inhibition of the enzyme in the tumor as well as in stromal cells, resulting in reduction of carcinogen production, anti-proliferative and pro-apoptopic actions within the tumor and anti-angiogenic and pro-immune surveillance activities in endothelial and myeloid cells. The combination of COX-2 inhibitor with standard cancer chemotherapeutic and / or radiation may provide additional therapeutic paradigms in the treatment of various human cancers.

The cyclooxygenase-2 (COX-2) enzyme catalyzes the rate-limiting step of prostaglandin formation in pathogenic states. The molecular regulation of COX-2 gene expression is normally tightly regulated on transcriptional and post-transcriptional levels. However, loss of function at either level of COX-2 gene regulation promotes constitutive COX-2 overexpression which plays a key role in carcinogenesis, particularly colorectal tumorigenesis. Current work investigating the regulatory mechanisms of COX-2 expression has demonstrated post-transcriptional regulation to play a central role. Rapid COX-2 mRNA decay and translational inhibition is mediated through a conserved AU-rich element (ARE) present within the 3'-untranslated region (3'UTR). The COX-2 ARE exerts its control through association with ARE RNA-binding proteins. These trans-acting regulatory factors influence the fate of COX-2 mRNA by controlling mRNA degradation, stabilization, or translation. Recent evidence demonstrates the functional significance rapid mRNA decay and translational inhibition play in controlling COX-2 gene expression and that, if dysregulated, allow for overexpression of COX-2 and other associated angiogenic factors detected in neoplasia.

Multidrug resistance (MDR) of cancer cells to cytostatic agents is the major obstacle for the succesfull chemotherapy. One of the causes of the development of cellular resistance to a wide variety of drugs is the elevated expression of membrane transporter proteins such as members of ATP binding cassette (ABC) protein superfamily. Expression of the ABC transporter MDR1, also termed P-glycoprotein (P-gp), seems to correlate with drug resistance of tumors to chemotherapy. Cyclooxygenase-2, an inducible isoform of enzyme, responsible for generation of prostaglandins from arachidonic acid, is constitutively expressed in a number of cancer cells. Anti-cancer potency of cyclooxygenase inhibitors is established, but the mechanism of Cox-2-dependent potentiation of tumor growth is a subject of intense discussion. Here we focus on the discussion of potential link between Cox-2 expression and development of multidrug resistance phenotype. Our observation, that enforced expression of Cox-2 causes enhancement in MDR1 expression and functional activity suggests the existence of causal link between Cox-2 activity and MDR1 expression. The use of Cox-2 inhibitors to decrease function of MDR1 may enhance accumulation of chemotherapy agents and decrease resistance of tumors to chemotherapeutic drugs.

The last decade has witnessed a rapid expansion in our understanding of the mammalian endogenous cannabinoid system. In just a few short years since the discovery of endogenous lipids that serve as cannabinoids in vivo, these molecules have been shown to participate in a broad array of physiological and pathological processes. Consequently, attention has been directed at defining the proteins responsible for endocannabinoid synthesis, transport, and metabolism. Recently, multiple fatty acid oxygenases including, most notably, cyclooxygenase-2 (COX-2), have been implicated in endocannabinoid metabolism. This review will highlight connections between COX-2 and the endogenous cannabinoid system. The available biochemical evidence supporting a role for COX-2 in endocannabinoid metabolism will be presented. Finally, the potential biological consequences of COX-2-mediated endocannabinoid oxygenation will be discussed.

Non-immunosuppressive immunophilin ligands (NI-IPLs) are attracting attention as new candidate drugs for neuroprotection and / or neurorestoration, particularly since they do not have the adverse effects of immunosuppressants. However, it is not yet enough to understand that NI-IPLs are useful drugs for treating neurological disorders. In particular, the molecular mechanism of NI-IPL activity in target cells in the brain remains obscure. In this review, we focused on the molecular basis of the neuroprotective properties of IPLs. Our findings suggest that IPLs have neuroprotective effects mediated by multiple beneficial properties such as a glutathione (GSH)-activating effect, a neurotrophic factor (NTF)-activating effect, and an anti-apoptotic effect, but not by an immunosuppressive effect, both in cell cultures and in vivo. In particular, the GSH-activating effect and the NTF-activating effect of NI-IPLs may be essential to the expression of their neuroprotective properties. Thus, NI-IPLs might have a potentially beneficial effect by ameliorating neurological disorders, since they do not cause serious side effects such as immune deficiency.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by cardinal features of tremor, bradykinesia, rigidity and postural instability. In addition to the motor symptoms patients experience cognitive decline eventually resulting in severe disability. Pathologically PD is characterized by neurodegeneration in the substantia nigra pars compacta (SNc) with intracytoplasmic inclusions known as Lewy bodies. In addition to the SNc there is neurodegeneration in other areas including cerebral cortex, raphe nuclei, locus ceruleus, nucleus basalis of meynert, cranial nerves and autonomic nervous system. Recent evidence supports the role of inflammation in Parkinson's disease. Apoptosis has been shown to be one of the pathways of cell death in PD. Minocycline, a tetracycline derivative is a caspase inhibitor, and also inhibits the inducible nitric oxide synthase which are important for apoptotic cell death. Furthermore, Minocycline has been shown to block microglial activation of 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned parkinsonism animal models and protect against nigrostriatal dopaminergic neurodegeneration. In this review, we present the current experimental evidence for the potential use of tetracycline derivative, minocycline, as a neuroprotective agent in PD.

We found that zonisamide (ZNS) has beneficial effects on Parkinson's disease (PD). ZNS is originally synthesized in Japan and has been used for over 10 years to treat intractable epilepsy. We administered 300 mg of ZNS to a patient with PD who incidentally had convulsive attacks. The attacks disappeared and, surprisingly, the parkinsonian symptoms improved dramatically. An open trial of ZNS (given in addition to their anti-PD drugs) in advanced PD patients clearly showed the lessening of symptoms, especially wearing-off. Although the effects gradually decreased after 1.5 years, more than 30% improvement of UPDRS total score was maintained up to 3 years. Nation-wide double-blind controlled study confirmed that the small dose (50mg / day) of ZNS improved all the cardinal symptoms of PD. As for its mechanism, we showed that ZNS increases dopamine contents in the striatum by activating dopamine synthesis and the level of mRNA of tyrosine hydroxylase (TH) prior to that of TH protein. ZNS moderately inhibits monoamine oxydase (MAO) B. It has no effects on dopamine receptors, dopamine transporter or dopamine release. ZNS has no direct effects on glutamate receptors, adenosine receptors, or serotonergic system, which have been suggested to be effective points of anti-PD drug other than dopamine system. Therefore, it is suggested that the activation of dopamine synthesis and the moderate level of MAOB inhibition are main mechanisms of ZNS effects on PD. ZNS has significant effects on T-type Ca++ channels and oxidative stress. They may also affect the beneficial action of ZNS on PD.

It is well known that nonsteroidal anti-inflammatory drugs (NSAIDs) possess antiinflammatory, analgesic and antipyretic properties by inhibiting cyclooxygenase (COX), a prostaglandin-synthesizing enzyme. It has also been revealed that NSAIDs exert inhibitory effects on the generating system of nitric oxide radicals and modulating effects on transcription factors which are related to inflammatory reactions including cytokine expression. Recently, a number of studies have been conducted focusing on the neuroprotective effects of NSAIDs, since it has been reported that inflammatory processes are associated with the pathogenesis of several neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. In the experimental model of Parkinson's disease, NSAIDs have also exerted neuroprotective effects which are based not only on their COX-inhibiting effects but also on other properties: inhibitory effects on nitric oxide synthesis, action as agonists for peroxisome proliferator-activated receptor g, and some unknown pharmacological effects. In this article, various pharmacological effects of NSAIDs except their inhibitory action on COX are reviewed, and possible neuroprotective effects of NSAIDs have been discussed on neurodegenerative diseases, especially Parkinson's disease.