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AbstractDrug resistance and toxicity are the most widespread limitations in the pursuit of sufficient antitumor effectiveness and successful control of oncological diseases, including colorectal cancer (CRC). Herein the objective was to investigate some hematological side effects of the chemotherapeutic regimen FOLFOX-4, their relation to dihydropyrimidine dehydrogenase (DPD) levels and the associated alterations in CRC patients’ plasma free-radical scavenging properties and extent of oxidative molecular damage. Thirty-eight patients with histologically confirmed CRC diagnoses, assigned to chemotherapy with the FOLFOX-4 regimen, were recruited. The diagnostic methods included a complete physical examination, blood routine test and general biochemistry. The DPD levels were assayed. The patients’ plasma free-radical scavenging properties and extent of molecular oxidative damage were determined by spectrophotometry and enhanced chemiluminescence. The clinico-pathological and demographics characteristics of the patients were in agreement with the reports from retrospective cohort studies. The FOLFOX-4 regimen induced a decrease in plasma free-radical scavenging properties and increased extent of lipid peroxidation. White blood cells, granulocytes and lymphocytes decreased significantly after the first cycle of the therapy. The patients’ DPD level decreased statistically significantly in the case of severe reduction (more than 25%) of white blood cells and granulocyte counts. The obtained data are in agreement with already known facts concerning the side effects of the FOLFOX-4 regimen and associated changes in redox homeostasis. Genetic predisposition to effectively metabolize and tolerate the applied therapy, i.e. DPD levels, could modulate some aspects of the observed changes in the aforementioned parameters.

AbstractWe have recently identified several aroylhydrazone-based molecular hybrids with antiseizure activity. We aimed to investigate the analgesic activity of these molecules further. Male ICR mice were injected intraperitoneally with the tested substances or with the vehicle only (controls). We performed hot plate tests, formalin test and maximal electroshock (MES) test and further studied the cytokine proteome in the brain. In silicoanalysis was performed for prediction of the physicochemical parameters and activity. The furan-substituted aroylhydrazone-based 2H-chromene hybrid showed a significant increase of the latent time as compared with the baseline values (p< .05). Both the chlorine-substituted and the methyl-substituted aroylhydrazone-based coumarin derivatives significantly decreased the first phase of the formalin test (p< .05). We also found suppression of all the cytokines which were overexpressed in the model of acute seizures (MES test) and in the formalin paw test. The in silicomodel predicted hydroxymethylglutaryl coenzyme A synthetase 2 (HMGCS2) enhancer activity. Further testing is needed to confirm the mechanism of the potentially beneficial effects of the tested substances and to evaluate the toxicity and efficacy of the proposed molecules.

ABSTRACTEpilepsy is one of most reported neurological disorders after migraine, stroke and Alzheimer's disease. Empiric clinical data reveal that seizures and epilepsy more likely affect men than women. The aim of present study was to investigate the effect of steroid adrenal and gonadal hormones on the intensity, dynamics and latency of kainic acid-evoked seizure and lethality in a rat model of epileptogenesis. After surgical adrenalectomy/gonadectomy, male rats were at randomassorted in groups and treated from postoperative day 1 to day 5 with corticosterone (30 mg/kg), estradiol (0.03 mg/kg), progesterone (75 mg/kg), dihydroprogesterone (75 mg/kg) and dihydrotestosterone (0.75 mg/kg). Spontaneous recurrent seizures generated by kainic acid were assessed. The treatment with corticosterone eliminated the aggravation of kainic acid-evoked seizures produced by adrenalectomy/gonadectomy. The application of corticosterone decreased the seizure intensity by 31% and prevented seizure-associated animal death. The effect of estradiol treatment was quite opposite. Estradiol treatment exacerbated the somatic and behavioural aspects of kainic acid-evoked epilepsy-like syndrome. The hormone increased the intensity of kainic acid-evoked seizures by 31%, decreased the latency of clonic weak seizures by 49% and enhanced the associated lethality by 133%. The treatment with progesterone or dihydroprogesterone produced minor alterations in intensity and latency of kainic acid-evoked seizures in the operated male rats. The application of dihydrotestosterone significantly aggravated the kainic acid-evoked seizures. In summary, hormonal unbalance could play an important role for seizure susceptibility in epileptogenesis. Corticosterone has better anti-seizure activity than progesterone and testosterone has significant pro-convulsive activity.

ABSTRACTPregabalin and gabapentin are amino-acid derivatives of gamma-aminobutyric acid. They have a high affinity to the α2δ protein in the central nervous system and both have been shown to be effective for neuropathic pain disorder. The aim of this study was to investigate the efficacy of gabapentin and pregabalin in animal models of neuropathic pain, and to correlate with clinical outcomes in patients with diabetic neuropathy. Gabapentin (60 mg/kg) and pregabalin (30 mg/kg) attenuate mechanical, tactile and heat hypersensitivity in rats with chronic constriction injury of the sciatic nerve and streptozotocin (STZ)-induced diabetes. There is no evidence that one of the drugs is superior to another at the different rat models and tests. In the incisional pain model, there was partial efficacy of gabapentin. Our clinical data suggest that relative to the baseline pain score, the treatment with pregabalin at doses of 300 mg/day or gabapentin at doses of 900 mg/day would be effective and well tolerated in patients diagnosed with moderate diabetic polyneuropathy. The study suggested that pregabalin may provide better analgesic outcomes than gabapentin on the sixth month of treatment. In conclusion, the comparative effects of gabapentinoids in animal models of neuropathic pain and neuropathic patients are suggestive of similar pathophysiological mechanisms being involved, but successful outcome is determined by a patient's individuality and the drug nature as well as the drug tolerability.

Opioid and non-opioid effects of acute and chronic morphine administration on behaviour, cardiovascular responses, cell proliferation and apoptosis and nitric-oxide synthase (NOS) activity were studied in rats. A novel score-point scale was introduced to quantify the signs of opioid withdrawal syndrome. NOS inhibitor L-NAME (NG-nitro-L-arginine methyl ester) was applied to reveal the role of NOS/NO pathway in the modulation of morphine-induced in vivoand in vitroresponses. The obtained data showed that chronic co-administration of L-NAME drastically attenuated naloxone-precipitated withdrawal syndrome and prevented the development of morphine tolerance to cardiovascular action of morphine. The apoptotic process was very much restricted by L-NAME supplementation of chronic morphine treatment, which resulted in few apoptotic cells, less low molecular weight genomic DNA and preservation of high molecular weight non-fragmented genomic DNA. The study provides new data for nitroxidergic modulation of opioid tolerance and dependence.

ABSTRACTIn exaggerated pain states, the activated astrocytes release several signalling molecules involved in cellular mechanisms of chronic pain. Among them, nerve growth factor (NGF) and interleukin (IL)-1β are both recognized as potent algogens. We previously showed that histamine is a potent stimulator of NGF production in rat cortical astrocytes in primary culture. Since histamine and IL-1β have common interactions in different physiological responses, in the present work we were interested to elucidate the molecular mechanisms involved in the interactions between histamine, IL-1β and NGF that could contribute to the processing of chronic pain. As an experimental model we used cultured rat cortical astrocytes. NGF and IL-1β levels in the culture medium were measured by ELISA. IL-1β mRNA expression was determined by RT PCR.The results showed that the co-treatment of the cultured astrocytes with histamine and IL-1β significantly increased NGF secretion in comparison to the secretion observed with either histamine, or IL-1β alone. The histamine and IL-1β effect on NGF secretion was additive, dose-dependent and increased with increased concentrations of either histamine, or IL-1β. The additive effect of histamine and IL-1β on NGF secretion was strongly suppressed by histamine H1 receptor antagonist/inverse agonist mepyramine, protein kinase C (PKC) inhibitors (GF 109203X, Go 6976), and mitogen-activated protein kinase kinase (MAPK)-1 inhibitor (PD 98059); however, they did not influence significantly the NGF secretion evoked by IL-1β alone. Histamine also stimulated the secretion of IL-1β from cultured astrocytes and induced higher expression of IL-1β mRNA in comparison to untreated cells.We concluded that histamine potently interacts with the synthesis and secretion of IL-1β and NGF in astroglial cells, and therefore can contribute to the development and maintenance of chronic pain, mediated by both algogens.

ABSTRACTPelvic pain is a complex painful sensation caused by spasm/distension/inflammation in hollow organs, with still unclear mechanisms. The aim of this study was to develop and validate an en block—ex situ mouse model resembling the conditions of painful distension of the urinary system and an in vitro rat model resembling uterine contractions in conditions of hormonal simulation of dysmenorrhea. The effects of Metamizol (Analgin) were studied in test experiments in order to validate the experimental potential of the novel en block—ex situ and in vitro models. Mature male mice (27.8 g ± 0.4 g b.m.) and female Wistar rats (180 g ± 5 g b.m.) were used. (i) The lumbar-sacral portion of spine and pelvis with whole urinary system (kidneys, ureters, urinary bladder, urethra) and surrounding tissues were dissected en block, placed in an organ chamber and bathed with tissue medium. The effect of Metamizol (0.25 mmol/L) on sensory nerve firing during rapid distension of urinary bladder was studied. (ii) Anesthetized rats were ovariectomized via ventral approach. Postoperatively, the animals were implanted with matrix-driven delivery system (MDDS) containing Levonorgestrel (1.05 mg) or placebo. MDDS was removed after 4 days (hormone withdrawal) or 7 days (placebo application). The middle part of the uterine horns was excised and placed between two platinum ring electrodes near the outlet of a 1 mL plastic double-jacketed horizontal tissue chamber. The preparation was tied to a force-displacement transducer for registration of isometric changes of tension. Electric stimulation was applied to elicit myogenic motor responses. Metamizol (0.5 mmol/L) was applied in vitro. The in vitro results showed that Metamizol suppressed the spontaneous, as well as the electrical field stimulation evoked and PGF2α- induced contractions of isolated uterine horn. Metamizol alleviated the firing of pelvic nerve afferents due to bladder distension and/or intravesical application of ATP, but did not change the distension induced release of ATP. The results revealed a therapeutic potential of Metamizol in alleviation of pain in painful pelvic syndromes in humans.