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The purpose of the present study was to examine whether the effects of chronic or acute exposure to cadmium on memory processes in mice could be exacerbated by transiently reducing cerebral oxygen supply. Adult mice were subjected to bilateral clamping of the carotid artery (BCCA) for 30 min under anesthesia. Cadmium chloride was administered intraperitoneally after surgery at single doses of: 0.7 mg/kg (low dose), 1.4 mg/kg (high dose), or at a prolonged dose of 0.7 mg/kg for up to 10 days. Long-term memory was evaluated in a step-through passive avoidance task while spatial working memory was evaluated using a Y-maze spontaneous alternation task. BCCA mice injected with the 1.4 mg/kg dose of cadmium exhibited recall deficits in the step-through passive avoidance task. Combined treatment at either dose had no effect on the acquisition of passive avoidance. In the Y-maze task, spontaneous alternation behavior was only impaired in BCCA mice treated with the prolonged cadmium dose. These results indicate that cerebral oligemic hypoxia may alter cadmium neurotoxicity and potentiate the tendency for cadmium-induced memory impairments in the passive avoidance task and spontaneous alternation deficits.

The effects of adenosine A3 agonist IB-MECA on scopolamine- and MK-801-induced impairment of spontaneous alternation and learning abilities were examined using Y-maze and passive avoidance tasks in mice. IB-MECA given 20 min before test had no effect on spontaneous alternation performance. Similarly learning abilities tested in passive avoidance were not disturbed after IB-MECA administration before training session. IB-MECA significantly diminished scopolamine- and MK-801-induced impairment of spontaneous alternation in Y-maze and learning abilities in passive avoidance task as well as reduced higher locomotor activity in MK-801-treated group. This ameliorating effect of IB-MECA was not antagonised by adenosine A1 antagonists CPX. Obtained results indicate that adenosine A3 receptor stimulation may ameliorate spatial memory and long term memory impairments in terms of cholinergic and glutamatergic deficits induced by scopolamine and MK-801, respectively.

Hypoxia of the brain may alter further seizure susceptibility in a different way. In this study, we tried to answer the question how episode of convulsion induced by hypoxia (HS) changes further seizure susceptibility, and how N-methyl-D-aspartic acid (NMDA) and AMPA/KA receptor antagonists influence this process. Adult Albino Swiss mice exposed to hypoxia (5% O(2)) developed clonic/tonic convulsions after about 340 s. Mice which underwent 10 s but not 5 s seizures episode subsequently exhibited significantly increased seizure susceptibility to low doses (equal ED(16)) of bicuculline (BCC) and NMDA during a 3-week observation period. No morphological signs of brain tissue damage were seen in light microscope on the third day after a hypoxia-induced seizure (HS). Learning abilities assessed in passive avoidance test as well as spontaneous alternation were not disturbed after an HS episode. Pretreatment with AMPA/KA receptor antagonist NBQX effectively prolonged latency to HS and given immediately after seizure episode also attenuated subsequent convulsive susceptibility rise, however, NMDA receptor antagonist, MK-801, appeared to be ineffective. These results suggest that a seizure episode induced by hypoxia, depending on its duration, may play an epileptogenic role. The AMPA/KA receptor antagonist prolongs the latency to HS, and given after this episode, prevents the long-term epileptogenic effect.

Synthesis of 2-[2-hydroxy-3-(4-aryl-1-piperazinyl)propyl] derivatives of 4-alkoxy-6-methyl-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-diones (8-12) is described. The chlorides used in the above synthesis can exist in two isomeric forms: chain (18-20) and cyclic (19a, 20a). The compounds 8-12 exhibited potent analgesic activity which was superior than that of acetylsalicylic acid in two different tests. Most of the investigated imides suppressed significantly spontaneous locomotor activity in mice.

The aim of the study was to assess the influence of chronic treatment with a non-metabolisable glucose analogue, 2-deoxyglucose (2-DG) at a 150 mg/kg dose on long-term epileptic tolerance (ET) evoked by 30 min bilateral carotid artery clamping (BCCA) in mice. The effects of protein synthesis inhibition with cycloheximide (CHX), given in three daily doses of 2.5 mg/kg starting either 1 day before (peri-insult regimen) or 1 day after the priming insult (post-insult regimen), on ET development was also studied. Seizures were induced 14 days after BCCA with 3.5 mg/kg of bicuculline; this dose (CD97) evokes convulsions in 97% of normal untreated mice. BCCA resulted in decreased mortality, prolonged latency to the onset of generalised convulsions and decreased overall seizure score. CHX given in the post-insult regimen did not influence, while the peri-insult regimen abolished, all signs of BCCA-evoked ET. 2-DG treatment of sham-operated animals resulted in a moderate but significant decrease in mortality rate and a tendency toward a lower seizure score. BCCA combined with 2-DG treatment resulted in a marked decrease in mortality rate, as well as reduction in all indicators of seizure susceptibility. CHX abolished the antiepileptic effects of BCCA alone, as well as BCCA combined with 2-DG, while it did not influence the 2-DG-related decrease in mortality. We conclude that the development of BCCA-induced epileptic tolerance, as well as unmasking antiepileptic effects of 2-DG by BCCA, is dependent on protein synthesis.

The synthesis of N-aryl(heteroaryl)piperazinylalkyl derivatives of imide of 2-(1-piperidino)-3,4-pyridinedicarboxylic acid is reported. 3 examined compounds proved to be active pharmacologically in some tests.

Derivatives of the pyrazolopyridothiazine-5,5-dioxide 6 and the pyrido- thiazine-1,1-dioxide 2 bearing 4-phenyl-(heteroaryl)-1-piperazinylpro- pyl substituent at the nitrogen of the thiazine ring were synthesized. The acute toxicity and preliminary results of the CNS activity of some derivatives 2 and 6 are described. A structure-activity relationship is discussed

Starting from pyridothiazines 1 and N-methyl(phenyl)hydrazines isomeric derivatives 2 and 3 of the pyrazolo[4,3-c]pyrido[3,2-e]-1,2-thiazine, a new heterocyclic ring system, have been obtained. The structure of the synthesized compounds was confirmed by spectroscopic and elemental analyses. The results of the preliminary pharmacological study of CNS effects caused by compounds 2 are reported.

The synthesis of N-aryl(pyrimidinyl)piperazinylalkyl(hydroxyalkyl) derivatives of 1,4-dioxo(1,4,5-trioxo)-1,2,3,4-tetra (and 1,2,3,4,5,6-hexa)hydropyrido[3,4-d]pyridazines is described. Some of them show biological activity in the preliminary pharmacological tests.

As an extension of our previous work we describe the synthesis and pharmacological investigation of a new series of derivatives of pyrrole-3,4-dicarboximide possessing the 4-substituted-piperazin-1-ylalkyl group linked to the imide nitrogen. The products were evaluated for acute toxicity, and effectiveness in a series of CNS and arterial blood pressure tests. The preliminary pharmacological screening was determined in animal models. Several compounds demonstrated moderate to high analgesic activity in the ‘writhing syndrome’ test ( 5f -1/640 LD 50 ). Some of the structure–activity relationships are also discussed.

As a continuation of our work on N-[4-aryl(heteroaryl)piperazin-1-ylalkyl]-3,4-pyrro ledicarboximides, which were characterized by strong analgesic activity and CNS depressive action, several novel N-substituted 3,4-pyrroledicarboximides were prepared and eleven representatives were examined in a series of in vivo CNS tests. A few of these compounds displayed a similar profile of biological selectivity to that of 3,4-pyrroledicarboximides described previously; their structure-activity relationships are discussed.

Recently we reported on 2 H -4,6-dimethyl-2-[(4-phenylpiperazin-1-yl)methyl]-3-oxo-2,3-dihydroisothiazolo[5,4- b ]pyridine ( V ), which exhibited high anorectic action in animal models as a result of stimulation of serotoninergic system. This paper describes the synthesis of the series 3 – 5 of analogues of V prepared from 2-hydroxymethyl-4,6-dimethylisothiazolopyridine ( 2 ) and corresponding 4-substituted-piperazines(piperidines) or tetrahydroisoquinoline. The 12 compounds obtained were screened in standard CNS tests in in vivo (mice and rats). In contrast to V , none of its analogues showed serotoninergic activity, whereas several of these compounds were found to be active as weak to moderate analgesic agents. According to X-ray and molecular modeling studies the different pharmacological profile of V and its o -OCH 3 analog 3a , taken as an example, should be referred back to the conformational restriction incorporated by the o -substitution rather than effects of different lipophlicity or basicity of these compounds.

The anticonvulsive activity of nociceptin, endogenous OP4 receptors agonist was investigated in pentylenetetrazole (PTZ), N-methyl D-aspartic acid (NMDA), bicucculine (BCC) and electrically evoked seizure models of experimental epilepsy. Nociceptin, at the dose of 10 nmol, suppressed the clonic seizures induced by PTZ, NMDA and BCC. [Phe1(psi)(CH2-NH)Gly2]nociceptin-(1-13)-NH2 which has been proposed to be selective antagonist OP4 receptors, did not prevent the action of nociceptin. The effect of [Phe1(psi)(CH2-NH)Gly2]nociceptin-(1-13)-NH2 on seizures induced by PTZ, NMDA and BCC was very similar to that of nociceptin. These data support the hypothesis that it possesses agonistic properties. Naloxone did not reverse the anticonvulsive action of nociceptin as well as [Phe1(psi)(CH2-NH)Gly2]nociceptin-(1-13)-NH2 which excludes the participation of opioid receptor in this action. On the other hand in the electroconvulsive model of generalized seizures, nociceptin as well as [Phe1(psi)(CH2-NH)Gly2]nociceptin-(1-13)-NH2 influenced neither the electroconvulsive threshold nor the maximal electroshock test. The data suggest that nociceptin and [Phe1(psi)(CH2-NH)Gly2]nociceptin-(1-13)-NH2 can exert anticonvulsive action. These properties depend on OP4 but not opioid receptors activation.

Recently we reported on 2 H -4,6-dimethyl-2-[(4-phenylpiperazin-1-yl)methyl]-3-oxo-2,3-dihydroisothiazolo[5,4- b ]pyridine ( V ), which exhibited high anorectic action in animal models as a result of stimulation of serotoninergic system. This paper describes the synthesis of the series 3 – 5 of analogues of V prepared from 2-hydroxymethyl-4,6-dimethylisothiazolopyridine ( 2 ) and corresponding 4-substituted-piperazines(piperidines) or tetrahydroisoquinoline. The 12 compounds obtained were screened in standard CNS tests in in vivo (mice and rats). In contrast to V , none of its analogues showed serotoninergic activity, whereas several of these compounds were found to be active as weak to moderate analgesic agents. According to X-ray and molecular modeling studies the different pharmacological profile of V and its o -OCH 3 analog 3a , taken as an example, should be referred back to the conformational restriction incorporated by the o -substitution rather than effects of different lipophlicity or basicity of these compounds.

Preconditioning is defined as an adaptive mechanism produced by short periods of hypoxia/ischemia, resulting in protection against subsequent ischemic insult, and development of seizures. Results of the present study demonstrate that an episode of normobar hypoxia reduces the susceptibility to convulsions induced by pentylenetetrazol (PTZ) 30 min, 24 h, as well as 4 and 7 days later. Administration of morphine showed similar effects after 24 h. Naloxone, given before ischemic preconditioning, as well as morphine, blocked the development of the protection. Administration of D-Ala-Met-enkephalin-Gly-ol (DAMGO - a selective mu-opioid receptor agonist), as well as trans-3, 4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl) cycloexilbenzeneacetamide ethane sulfonate] (U-69,593 - a selective kappa-opioid receptor agonist), mimicked the effects of hypoxic preconditioning (HPC). (-)-N-(Cyclopropylmethyl)-4,14-dimethoxymorphinan-6-one (cyprodime - a selective mu-opioid receptor antagonist, as well as nor-binaltorphimine dihydrochloride (nor-BNI - selective kappa-opioid receptors antagonist), given before HPC as well as before respective opioid receptor agonists, blocked the development of the protection. This study provides evidence that mu- and kappa-opioid receptors are involved in HPC against seizures in the brain.

The aim of the study was to examine the role of NMDA receptors in modulation of protective effect against bicuculline toxicity after transient brain ischemia in mice. Animals were exposed for 30 min to bilateral clamping of the common carotid arteries (BCCA) in anaesthesia. MK-801 was administered intraperitoneally in two paradigms: a) acute treatment: twice, 1.0 mg/kg; 1 hour before clamping and 6 hours after re-circulation and b) chronic treatment: 0.1 mg/kg; started 24 hours after re-circulation and continued once daily for 13 days, the last injection was administered 24 hours before seizure induction. 14 days after BCCA, the animals were injected with bicuculline (3.5 mg/kg s.c). A significant decrease in seizure susceptibility could be observed in BCCA treated mice compared with sham-operated controls. Acute treatment with MK-801 did not affect seizure activity both in sham and BCCA mice. Chronic treatment with the drug potentiated anticonvulsant effect of brain ischemia but had no influence on seizure activity in sham-operated mice. The analysis of GABA content in brain tissue performed 14 days after BCCA showed a moderate increase in vehicle-treated mice and significant elevation after chronic treatment with MK-801. It can be suggested that NMDA receptors are not involved in the induction of a protective effect against bicuculline toxicity after transient brain ischemia. The prolonged treatment with low doses of MK-801 may potentiate a developed process in a mechanism of chemical preconditioning.

We have synthesized several new isothiazolopyridines possessing a side chain at the isothiazole ring typical, among others, for trazodone or NAN-195. Representatives of the novel isothiazolopyridines were examined for acute toxicity and in several commonly used CNS tests in mice and for arterial blood pressure in rats. Three of the five compounds tested showed significant analgesic activity. The most active compound (3b) exhibited analgesic action in the "writhing" test in a dose 1/1280 of LD50 (LD50 = 1135.5 mg/kg) after administration i.p. to mice. Additionally, the compounds described here and related isothiazolopyridines obtained previously were evaluated against Mycobacterium tuberculosis H37Rv at 12.5 micrograms/ml in in vitro assays. Seven of the nineteen compounds tested showed 100% inhibition of that mycobacterium.

The synthesis of 1-(4-substituted)butyl derivatives of amides of 7-methyl-3-phenyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3- d ]pyrimidine-5-carboxylic acid and the results of the preliminary pharmacological screening are described in this paper. Some of them showed a weak analgesic action and caused suppression of the spontaneous locomotor activity of mice.

Synthesis of amides of 7-methyl-3-phenyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-5-carboxylic acid (6–10) and their 1-[2-hydroxy-3(4-phenyl-1-piperazinyl)propyl] derivatives (11–15) are described. Some of them displayed strong analgesic activity.

As an extension of our previous work we describe the synthesis and pharmacological investigation of a new series of derivatives of pyrrole-3,4-dicarboximide possessing the 4-substituted-piperazin-1-ylalkyl group linked to the imide nitrogen. The products were evaluated for acute toxicity, and effectiveness in a series of CNS and arterial blood pressure tests. The preliminary pharmacological screening was determined in animal models. Several compounds demonstrated moderate to high analgesic activity in the ‘writhing syndrome’ test ( 5f -1/640 LD 50 ). Some of the structure–activity relationships are also discussed.

The 2-[3-(substituted-amino)-2-hydroxypropyl]-4,6-dimethyl-3-oxo-2,3- dihydroisothiazolo[5,4-b]pyridines 3 were synthesized and pharmacologically evaluated in animal models. The preliminary pharmacological screening study showed that the investigated compounds were toxic and had no significant activity in central nervous system (CNS) tests. Additionally, compounds 3, and several other 2-substituted-4,6- dimethyl-3-oxo-2,3-dihydroisothiazolo[5,4-b]pyridines described here (2), together with those (4) reported in a previous paper, were evaluated in vitro against Mycobacterium tuberculosis H37Rv. For comparison, products of the rearrangement of some isothiazolopyridine 1,1-dioxides (4a,b) with the corresponding pyrido[3,2-e]-1,2-thiazines (5a,b) and different N2-substituted derivatives of the latter (5c-i) were also prepared and investigated in antimycobacterial tests. The most potent antituberculars of the 23 compounds assayed are 2-[3-(4-benzylpiperidin-1-yl)-2-hydroxypropyl]-4,6-dimethyl-3-oxo- 2,3- dihydroisothiazolo[5,4-b]pyridine 3d and ethyl (4,6-dimethyl-3-oxo-2,3-dihydroisothiazolo[5,4-b]pyridin-2-yl)acet ate 4c (MIC < 12.5 micrograms/ml, 100 and 98% inhibition, respectively).

The synthesis of tetra(hexa)hydropyrazolo[1,2-a]pyrido[3,4-d]pyridazine derivatives (14-21) and the results of pharmacological screening are described in this paper. All compounds tested were non-toxic and showed a significant analgesic action. The analgesic effects were associated with the suppression of the spontaneous locomotor activity. Furthermore most of the synthesized compounds displayed a weak antimycobacterial action in the preliminary screening.

The effects of citicoline and/or low dose of MK-801 (sufficient to prevent the development of seizures) on survival, neurological and behavioral recovery following transient hyperglycemic–oligemic–hypoxic insult have been evaluated in mice. Neurological recovery was assessed semi-quantitatively on the third and the 10th day after the insult, and behavioral tests evaluating spontaneous locomotor activity, motor coordination and spontaneous alternation performance were performed on day 10. Neither drug given alone did influence survival rate, but the combination of MK-801 and higher citicoline dose decreased mortality on day 10. Behavioral performance was markedly compromised by the insult. Citicoline, but not MK-801, slightly but significantly improved behavioral outcome in all three tests. Conclusion: when brain ischemic insult is complicated with acute hyperglycemia, post-treatment with citicoline combined with MK-801 in low anti-convulsive dose improves survival and neurological recovery, and citicoline but not MK-801 enhances behavioral recovery.