Andrzej Moniczewski

Oxidative Stress in Neurodegenerative Diseases

The pathophysiologies of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), and Alzheimer’s disease (AD), are far from being fully explained. Oxidative stress (OS) has been proposed as one factor that plays a potential role in the pathogenesis of neurodegenerative disorders. Clinical and preclinical studies indicate that neurodegenerative diseases are characterized by higher levels of OS biomarkers and by lower levels of antioxidant defense biomarkers in the brain and peripheral tissues. In this article, we review the current knowledge regarding the involvement of OS in neurodegenerative diseases, based on clinical trials and animal studies. In addition, we analyze the effects of the drug-induced modulation of oxidative balance, and we explore pharmacotherapeutic strategies for OS reduction.

Oxidative stress as an etiological factor and a potential treatment target of psychiatric disorders. Part 2. Depression, anxiety, schizophrenia and autism

The pathophysiology of psychiatric diseases, including depression, anxiety, schizophrenia and autism, is far from being fully elucidated. In recent years, a potential role of the oxidative stress has been highlighted in the pathogenesis of neuropsychiatric disorders. A body of clinical and preclinical evidence indicates that psychiatric diseases are characterized by higher levels of oxidative biomarkers and with lower levels of antioxidant defense biomarkers in the brain and peripheral tissues. In this article, we review current knowledge on the role of the oxidative stress in psychiatric diseases, based on clinical trials and animal studies, in addition, we analyze the effects of drug-induced modulation of oxidative balance and explore pharmacotherapeutic strategies for oxidative stress reduction.

Transient Receptor Potential Channels - Emerging Novel Drug Targets for the Treatment of Pain

In mammals several members of the Transient Receptor Potential channel family (TRPs), expressed mainly in the sensory neurons and skin keratinocytes, are implicated in relevant physiological functions, including thermosensation,nociception and vision. Since the TRPV1-4, TRPA1 and TRPM8 channels from this family play a pivotal role in both the detection and possibly modulation of painful stimuli, they are regarded as a very promising target of novel analgesic drugs. A few agents acting at TRPs, such as capsaicin or menthol, have a long history of their application as analgesics,whereas others (e.g. SB705498, JTS653, JNJ17203212, AP18, A967079, Chembridge-5861528 or PBMC) are currently being evaluated both in animals and in humans. In this review we discuss pain physiology, as well as the pharmacological properties of the TRPs involved in pain detection as potential critical peripheral analgesic targets. We present one of the most relevant strategies in the search for novel analgesic drugs, namely the TRP channels and their ligands, both agonists and antagonists as potential novel therapeutics for inflammatory and neuropathic pain syndromes. The safety profile of these agents, in particular their impact on thermosensation, is also discussed below.

Analgesic, anticonvulsant and antioxidant activities of 3-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-dihydrofuran-2-one dihydrochloride in mice

Recently we have shown that 3-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-dihydrofuran-2-one dihydrochloride (LPP1) is an antinociceptive and local anesthetic agent in rodents. Below an extended study of the pharmacological activity of LPP1 is described. In vitro LPP1 has no affinity for GABA(A), opioidergic μ and serotonergic 5-HT(1A) receptors. The total antioxidant capacity of LPP1 (1-10mM) measured as ABTS radical cation-scavenging activity showed that LPP1 has dose-dependent antioxidant properties in vitro. Low plasma concentration of this compound detected by means of HPLC method 30min after its intraperitoneal administration suggests a rapid conversion to metabolite(s) which may be responsible for its analgesic and anticonvulsant activities in vivo. In vivo the compounds influence on the electroconvulsive threshold and its activity in the maximal electroshock seizure test (MES) were evaluated. The results demonstrated that LPP1 had an anticonvulsant activity in the MES model (ED(50)=112mg/kg) and at a dose of 50mg/kg was able to elevate the electroconvulsive threshold for 8mA as compared to the vehicle-treated mice. The analgesic activity of LPP1 was investigated in the acetic acid-induced writhing test in two groups of mice: animals with sensory C-fibers ablated, and mice with C-fibers unimpaired. It proved the potent activity of this compound in both groups (approximately 85% as compared to the vehicle-treated mice). The adverse effects of LPP1 were evaluated as acute toxicity (LD(50)=747.8mg/kg) and motor coordination impairments in the rotarod and chimney tests. The results from these tests show that LPP1 at doses higher than 100mg/kg is likely to impair the motor performance of experimental animals. Concluding, LPP1 is an analgesic and anticonvulsant compound which has antioxidant properties in vitro. Further studies are necessary to assess whether the antioxidant activity and the receptor profiling demonstrated in vitro can be confirmed for its metabolite(s) that are formed in vivo.

Oxidative stress as an etiological factor and a potential treatment target of psychiatric disorders. Part 1. Chemical aspects and biological sources of oxidative stress in the brain

Oxidative stress is a dysfunctional state of living cells, caused by the disturbance of the pro-/antioxidative equilibrium. This dynamic equilibrium, constitutive for all aerobic organisms, is an inevitable necessity of maintaining the level of oxidative factors on non-destructive value to the cell. Among these factors reactive oxygen species (ROS) and reactive nitrogen species (RNS) are the best known molecules. This review article shows the current state of knowledge on the chemical specificity, relative reactivity and main sources of ROS and RNS in biological systems. As a Part 1 to the report about the role of oxidative stress in psychiatric disorders (see Smaga et al., Pharmacological Reports, this issue), special emphasis is placed on biochemical determinants in nervous tissue, which predisposed it to oxidative damage. Oxidative stress can be identified based on the analysis of various biochemical indicators showing the status of antioxidant barrier or size of the damage. In our article, we have compiled the most commonly used biomarkers of oxidative stress described in the literature with special regard to potentially effective in the early diagnosis of neurodegenerative processes.

An overview of the pharmacological properties and potential applications of natural monoterpenes.

Monoterpenes, the major components of essential oils, belong to the group of isoprenoids containing ten carbon atoms. Being widely distributed in the plant kingdom they are extensively used in cuisine and human health care products. Studies have shown that both natural monoterpenes and their synthetic derivatives are endowed with various pharmacological properties including antifungal, antibacterial, antioxidant, anticancer, antiarrhythmic, anti-aggregating, local anesthetic, antinociceptive, anti-inflammatory, antihistaminic and anti-spasmodic activities. Monoterpenes act also as regulators of growth, heat, transpiration, tumor inhibitors, inhibitors of oxidative phosphorylation, insect repellants, feline and canine attractants and antidiabetics. These interesting activities which might be potentially used not only in pharmaceutical, but also food and cosmetic industries are discussed below.

Analgesic, antioedematous and antioxidant activity of γ-butyrolactone derivatives in rodents.

In this paper, the analgesic, antioedematous, motor-impairing and antioxidant properties of four &ggr;-butyrolactone derivatives (BM113, BM113A, BM138 and BM138A) are described. Pain was induced by thermal (hot-plate test), chemical (writhing test) or mechanical (Randall–Selitto model) stimulation. All in-vivo assays were carried out in mice pretreated intraperitoneally with the test compounds, except for the evaluation of anti-inflammatory and analgesic activities in the carrageenan-induced paw oedema model, in which rats were pretreated orally with these compounds. In the hot-plate assay, BM113A and BM138A dose dependently prolonged the latency of the nociceptive reaction. Their analgesic activity, measured as a median effective dose (ED50=4.7 mg/kg), was similar to that of morphine (2.4 mg/kg). In the writhing test, all four compounds, in particular BM113A and BM138A, showed higher potency than the reference drug acetylsalicylic acid (the ED50 values were 3.7, 2.3 and 46.1 mg/kg, respectively). BM138 caused a dose-dependent diminution of paw oedema (up to 49%) in the carrageenan model and BM138A at 200 mg/kg reduced mechanical hyperalgesia in the Randall–Selitto test (∼30% when compared with the control). None of the &ggr;-butyrolactone derivatives tested at the ED50 obtained in the hot-plate test influenced the locomotor activity of mice, although in the rotarod test at 24 rpm, BM113A and BM138 at 100 mg/kg showed some motor-impairing properties. In vitro, a concentration-dependent ABTS radical cation-scavenging activity of BM138 and BM138A (up to 80% inhibition of the radical absorbance) was observed. The results of the present study suggest that BM138 and BM138A could be of interest for future investigations as antinociceptive and antioedematous agents with potential free radical-scavenging properties.

Evaluation of the role of NMDA receptor function in antidepressant-like activity. A new study with citalopram and fluoxetine in the forced swim test in mice

BACKGROUND The NMDA/glutamate receptors are involved in the mechanism of antidepressant activity. METHODS The present study was designed to investigate the effect of NMDA receptor ligands (agonists and antagonists of glutamate sites) on the antidepressant-like activity of selective serotonin reuptake inhibitors (SSRIs), citalopram and fluoxetine, in the forced swim test in mice. RESULTS The antidepressant activity (reduction in immobility time) of citalopram but not of fluoxetine was antagonized by N-methyl-D-aspartate acid and enhanced by CGP37849 (antagonist of the NMDA receptor). CONCLUSIONS The present literature data indicate that the antidepressant-like activity of conventional antidepressants is generally affected by the NMDA receptor, although by modulation from different sites of the complex. Thus, it supports the issue of the ability of NMDA receptor antagonists to enhance the antidepressant action in human depression.

Evaluation of the irritating influence of carane derivatives and their antioxidant properties in a deoxyribose degradation test

Previous studies of the propranolol monoterpene derivative (-)-4-[2-hydroxy-3-(N-isopropylamino)-propoxyimino]-cis-carane hydrochloride (KP-23) and its diastereoisomers, KP-23R and KP-23S, demonstrated different effects on the cyclic AMP generating system as well as anti-inflammatory, analgesic, antihistaminic and antioxidant activity. The present study examined the influence of KP-23 and its diastereoisomers KP-23R and KP-23S on the skin-irritating activity and the mucous membrane-irritating activity as well as their influence on a late-type contact allergy in the in vivo tests. The hydroxyl radical scavenging potential of the three analogues was evaluated using their ability to inhibit Fe(II)/H2O2-induced oxidative degradation of 2-deoxyribose (2-DR) in the in vitro tests. The results obtained indicated that the hydroxyamine carane derivative did not evoke irritative changes and did not induce a late-type contact allergy in the guinea-pig. Diastereoisomers of KP-23 exhibit antioxidant properties in a dose-dependent manner and protected against OH-radicals generated from the Fenton reaction.

Strong antioxidant activity of carane derivatives

Oxidants play a significant role in causing oxidative stress, which underlies the pathogenesis of inflammation and rheumatoid arthritis. The processes associated with inflammatory responses are complex and often involve reactive oxygen species. There are many mediators that initiate and amplify the inflammatory response such as histamine, serotonin and metabolic products of arachidonic acid (thromboxane, prostaglandins and leukotrienes). In the present study, we examined the antioxidant activity of carane derivatives--KP-23 and its optical isomers--that possess strong local anesthetic and anti-inflammatory activity. The antioxidant effects (expressed as Trolox Equivalent Antioxidants Capacity, TEAC) were observed for one of the optical isomers of carane, a derivative of propranolol--KP-23R. The relative scavenging effect (%R) of ABTS+ by KP-23S, KP-23R and standards measured at 30 min was the following, listed in decreasing order: tetracaine > KP-23S > KP-23R > procaine > lignocaine > benzocaine (99, 85, 80, 38, 21 and 20%, respectively, at a concentration of 10 mM). The IC50 values also show strong antioxidant properties of the investigated KP compounds (ranging between 11-18 mM) and tetracaine (6.2 mM) compared to other local anesthetics (129-348 mM). Moreover, monoterpene derivatives were more effective as antioxidants than propranolol diastereoisomers (280-528 mM). We found that carane derivatives, in contrast to propranolol diastereoisomers, serve as potent antioxidants by scavenging radicals.