Effect of ACE inhibitors and AT1 receptor antagonists on pentylenetetrazole-induced convulsions in mice.

Experimental data show that some angiotensin-converting enzyme (ACE) inhibitors and angiotensin AT(1) receptor antagonists that are normally used as antihypertensive drugs can exert anticonvulsant-like activity against audiogenic seizures. In the current study, a number of ACE inhibitors (captopril, enalapril, cilazapril, perindopril and zofenopril) and AT(1) antagonists (losartan, telmisartan and candesartan) were examined against pentylenetetrazole (PTZ)-induced seizures in mice. Captopril (50 mg/kg) administered intraperitoneally significantly raised the PTZ threshold (p < 0.05). The remaining drugs were not protective against PTZ-induced convulsions. The current study indicates that captopril decreases PTZ-evoked seizures in mice, which is an animal model of myoclonic convulsions.

Homocysteine and cognitive disorders of postmenopausal women measured by a battery of computer tests--central nervous system vital signs.

The purpose of the study was the analysis of cognitive functions in postmenopausal women having different status of homocysteine levels by a battery of computer tests-central nervous system vital signs (CNS-VS). We examined whether homocysteine increases the risk of cognitive decline and which cognitive domains are more affected. We showed that the considerably better neurocognitive index was obtained by women with low homocysteine levels in comparison with those with hyperhomocysteinemia (p = 0.0017). Similarly, results were obtained in the field of executive functioning (p = 0.0011), complex attention (p = 0.0106), cognitive flexibility (p = 0.0016), and memory (p = 0.0145). Verbal memory and visual memory did not differ considerably among the studied groups. Also, we demonstrated that ε4/ε4 genotype was the most common (15.5 %) in women with hyperhomocysteinemia than in groups of patients with low (0 %) or normal (1.9 %) homocysteine levels. In summary, hyperhomocysteinemia was related with increased risk of decline in executive functioning, complex attention, cognitive flexibility, and memory in postmenopausal women.

Effects of the uremic toxin indoxyl sulfate on seizure activity, learning and brain oxidative stress parameters in mice.

Patients with end-stage renal disease often have neurological disorders, with a higher incidence of memory impairment or epilepsy than in the general population. Patients undergoing hemodialysis are particularly exposed to the biological effects of uremic toxins. Indoxyl sulfate (IS) is one of the most potent uremic toxins; however, its possible effects on seizure susceptibility or memory functions have yet to be elucidated. In the current study, we focused on investigating the possible convulsant and amnesic effects of IS in recognized animal models. The study was performed on adult male Swiss mice. IS and scopolamine (SCO) were administered intraperitoneally (i.p.), and pentylenetetrazole (PTZ) was injected subcutaneously (s.c.). All substances were given as single injections. Acute IS administration (400 mg/kg) led to its accumulation in the brain. IS at doses of 200 and 400 mg/kg decreased the PTZ convulsive threshold, and at the same doses, it did not significantly affect the threshold for electroconvulsions. IS (200 and 400 mg/kg) did not impair learning in the passive avoidance test and did not increase the SCO-induced memory impairment in this test. IS increased lipid peroxidation, decreased the level of reduced glutathione, and reduced the activity of superoxide dismutase and catalase in mouse brains. Exposure to IS did not significantly change the activity of acetylcholinesterase in the brain tissue. This study shows that acute exposure to IS induces oxidative stress in the brain and potentiates PTZ-induced seizures in mice. Further studies are needed to find out whether IS-induced oxidative stress may affect epileptic seizures and/or epileptogenesis.

Effect of combined treatment with diuretics and gabapentin on convulsive threshold in mice.

Research data show that diuretics can have anticonvulsant properties. This study examined effects of ethacrynic acid, a loop diuretic, and hydrochlorothiazide, a thiazide-type diuretic, on the anticonvulsant activity of gabapentin, a newer antiepileptic drug, in the maximal electroshock seizure threshold test in mice. Diuretics were administered intraperitoneally (ip.) both acutely (single dose) and chronically (once daily for seven days). Electroconvulsions were produced by an alternating current (50 Hz, 500 V, 0.2 s stimulus duration) delivered via ear-clip electrodes by a generator. Additionally, the influence of combined treatment with the diuretics and gabapentin on motor performance in the chimney test has been assessed. In the current study, ethacrynic acid at the chronic dose of 12.5 mg/kg and the single dose of 100 mg/kg did not affect the anticonvulsant activity of gabapentin. Similarly, hydrochlorothiazide (100 mg/kg), both in acute and chronic experiments, had no effect on the gabapentin action. On the other hand, in the chimney test, the combined treatment with ethacrynic acid (100 mg/kg) and gabapentin (50 mg/kg) significantly impaired motor performance in mice. Based on the current preclinical findings, it can be suggested that the diuretics should not affect the anticonvulsant action of gabapentin in epileptic patients. However, the combination of ethacrynic acid with gabapentin may cause neurotoxicity.

Oxidative Stress and Neurodegeneration in Animal Models of Seizures and Epilepsy.

Free radicals are generated in the brain, as well as in other organs, and their production is proportional to the brain activity. Due to its low antioxidant capacity, the brain is particularly sensitive to free radical damage, which may affect lipids, nucleic acids, and proteins. The available evidence clearly points to a role for oxidative stress in neuronal death and pathophysiology of epileptogenesis and epilepsy. The present review is devoted to the generation of free radicals in some animal models of seizures and epilepsy and the consequences of oxidative stress, such as DNA or mitochondrial damage leading to neurodegeneration. Additionally, antioxidant properties of antiepileptic (antiseizure) drugs and a possible use of antioxidant drugs or compounds in patients with epilepsy are reviewed. In numerous seizure models, the brain concentration of free radicals was significantly elevated. Some antiepileptic drugs may inhibit these effects; for example, valproate reduced the increase in brain malondialdehyde (a marker of lipid peroxidation) concentration induced by electroconvulsions. In the pentylenetetrazol model, valproate prevented the reduced glutathione concentration and an increase in brain lipid peroxidation products. The scarce clinical data indicate that some antioxidants (melatonin, selenium, vitamin E) may be recommended as adjuvants for patients with drug-resistant epilepsy.

Caffeine impairs anticonvulsant effects of levetiracetam in the maximal electroshock seizure threshold test in mice.

OBJECTIVES: Caffeine is the most widely used psychoactive substance in the world. Animal studies indicate that acute caffeine exposure at high doses may induce seizures and diminish the anticonvulsant activity of antiepileptic drugs (AEDs) at much lower doses. The aim of the current study was to assess the effect of caffeine on the anticonvulsant action of levetiracetam (LEV) and vigabatrin (VGB). METHODS: The anticonvulsant activity of LEV and VGB was examined in the maximal electroshock seizure threshold test in mice (MEST test). All drugs were administered intraperitoneally by single injections, and caffeine was applied at doses capable of interfering with AEDs. Effects of caffeine exposure on AEDs were also investigated in tests of memory and motor performance. RESULTS: Caffeine reduced the protective effect of LEV against electroconvulsions. Total brain concentration of LEV was unaffected by caffeine as well as inversely; LEV had no significant impact on the brain caffeine concentration, suggesting a pharmacodynamic nature of the interaction between LEV and caffeine in the MEST test. VGB at applied doses did not affect the convulsive threshold. Administration of VGB, but not LEV, alone or in combination with caffeine, impaired memory retention. In the chimney test, the combined treatment with AEDs and caffeine did not cause motor coordination impairment. CONCLUSIONS: It is suggested that caffeine may negatively affect the anticonvulsant action of LEV in patients with epilepsy.

Emerging therapeutic targets for epilepsy: preclinical insights.

INTRODUCTION: Around 30% of patients with epilepsy suffer from drug-resistant seizures. Drug-resistant seizures may have significant consequences such as sudden death in epilepsy, injuries, memory disturbances, and childhood learning and developmental problems. Available antiepileptic drugs (AEDs) work via numerous mechanisms - mainly through inhibition of voltage-operated Na+ and/or Ca2+ channels, excitation of K+ channels, enhancement of GABA-mediated inhibition and/or blockade of glutamate-produced excitation. However, the discovery and development of novel brain targets may improve the future pharmacological management of epilepsy and hence is of pivotal importance. AREAS COVERED: This article examines novel drug targets such as brain multidrug efflux transporters and inflammatory pathways; it progresses to discuss possible strategies for the management of drug-resistant seizures. Reduction of the consequences of blood brain barrier dysfunction and enhancement of anti-oxidative defense are discussed. EXPERT OPINION: Novel drug targets comprise brain multidrug efflux transporters, TGF-ß, Nrf2-ARE or m-TOR signaling and inflammatory pathways. Gene therapy and antagomirs seem the most promising targets. Epileptic foci may be significantly suppressed by viral-vector-mediated gene transfer, leading to an increased in situ concentration of inhibitory factors (for instance, galanin). Also, antagomirs offer a promising possibility of seizure inhibition by silencing micro-RNAs involved in epileptogenesis and possibly in seizure generation.

Assessment of drug-drug interactions between moxonidine and antiepileptic drugs in the maximal electroshock seizure test in mice.

Hypertension is a common comorbid condition with epilepsy, and drug interactions between antihypertensive and antiepileptic drugs (AEDs) are likely in patients. Experimental studies showed that centrally active imidazoline compounds belonging to antihypertensive drugs can affect seizure susceptibility. The purpose of this study was to assess the effect of moxonidine, an I1 -imidazoline receptor agonist, on the anticonvulsant efficacy of numerous AEDs (carbamazepine, phenobarbital, valproate, phenytoin, oxcarbazepine, topiramate and lamotrigine) in the mouse model of maximal electroshock. Besides, the combinations of moxonidine and AEDs were investigated for adverse effects in the passive avoidance task and the chimney test. Drugs were administered intraperitoneally (ip). Moxonidine at doses of 1 and 2 mg/kg ip did not affect the convulsive threshold. Among tested AEDs, moxonidine (2 mg/kg) potentiated the protective effect of valproate against maximal electroshock. This interaction could be pharmacodynamic because the brain concentration of valproate was not significantly changed by moxonidine. The antihypertensive drug did not cause adverse effects when combined with AEDs. This study shows that moxonidine may have a neutral or positive effect on the anticonvulsant activity of AEDs in patients with epilepsy. The enhancement of the anticonvulsant action of valproate by moxonidine needs further investigations to elucidate potential mechanisms involved.

Effect of caffeine on the anticonvulsant action of pregabalin against electroconvulsions in mice.

BACKGROUND: Experimental data indicate that caffeine (CAF) can reduce the anticonvulsant activity of antiepileptic drugs (AEDs) in animal models of seizures. The purpose of the current study was to examine the effect of CAF on the protective action of pregabalin (PGB) against electroconvulsions in mice. METHODS: Maximal electroshock seizure (MES) test was used in the current study. In addition, the combined treatment with CAF and PGB was assessed in the passive avoidance task (long-term memory) and the chimney test (motor coordination). Drugs were injected intraperitoneally (ip) as single injections. CAF was administered at doses reported to compromise the anticonvulsant action of AEDs in mice. RESULTS: CAF at a dose of 23.1 mg/kg reduced the anticonvulsant action of PGB in the MES test. The brain concentration of PGB was not significantly changed by CAF and vice versa. In the chimney test, CAF (23.1 mg/kg) protected mice against PGB-induced motor coordination impairment. CONCLUSIONS: Regarding seizure control, it might be suggested that patients with epilepsy treated with PGB should avoid taking CAF. The estimated total brain concentration of PGB and CAF does not suggest a pharmacokinetic interaction as an explanation for these results.

Understanding mechanisms of drug resistance in epilepsy and strategies for overcoming it.

INTRODUCTION: The present evidence indicates that approximately 70% of patients with epilepsy can be successfully treated with antiepileptic drugs (AEDs). A significant proportion of patients are not under sufficient control, and pharmacoresistant epilepsy is clearly associated with poor quality of life and increased morbidity and mortality. There is a great need for newer therapeutic options able to reduce the percentage of drug-resistant patients. AREAS COVERED: A number of hypotheses trying to explain the development of pharmacoresistance have been put forward. These include: target hypothesis (altered AED targets), transporter (overexpression of brain efflux transporters), pharmacokinetic (overexpression of peripheral efflux transporters in the intestine or kidneys), intrinsic severity (initial high seizure frequency), neural network (aberrant networks), and gene variant hypothesis (genetic polymorphisms). EXPERT OPINION: A continuous search for newer AEDs or among non-AEDs (blockers of efflux transporters, interleukin antagonists, cyclooxygenase inhibitors, mTOR inhibitors, angiotensin II receptor antagonists) may provide efficacious drugs for the management of drug-resistant epilepsy. Also, combinations of AEDs exerting synergy in preclinical and clinical studies (for instance, lamotrigine + valproate, levetiracetam + valproate, topiramate + carbamazepine) might be of importance in this respect. Preclinically antagonistic combinations must be avoided (lamotrigine + carbamazepine, lamotrigine + oxcarbazepine).

Developing precision treatments for epilepsy using patient and animal models.

Introduction: Phenytoin was the first antiepileptic drug (AED) discovered in an animal model of seizures whose clinical efficacy was subsequently confirmed. This clearly indicated that a search for other AEDs had to consider animal studies.Areas covered: Main seizure tests used for the evaluation of possible anticonvulsive activity of potential anticonvulsants and their predictive values have been reviewed. Procedures used for the estimation of antiepileptogenic effects have been also included.Expert opinion: First-line seizure models comprise maximal electroshock (MES)-, pentylenetetrazol (PTZ)- and kindling-induced convulsions in rodents. The MES test may be considered as a convenient and easy model of generalized tonic-clonic seizures, PTZ test - as a model of generalized myoclonic seizures and to a certain degree - absence seizures. Kindled seizures (for example, from amygdala) may be regarded as a model of focal seizures. Some tests have been suggested for the search of AEDs effective in drug-resistant seizures - for instance, 6 Hz (44 mA) test or intrahippocampal kainate model of mesial temporal lobe epilepsy. There are also recommendations from experimental epileptology on synergistic AED combinations for patients with drug-resistant seizures. The clinical evidence on this issue is scarce and favors a combined treatment with valproate + lamotrigine.

Captopril potentiates the anticonvulsant activity of carbamazepine and lamotrigine in the mouse maximal electroshock seizure model.

Some studies suggest a higher risk of hypertension in people with epilepsy. Captopril, a potent and selective angiotensin-converting enzyme (ACE) inhibitor, is a well known antihypertensive drug. Besides the peripheral renin-angiotensin system (RAS), ACE inhibitors are also suggested to affect the brain RAS which might participate in the regulation of seizure susceptibility. The purpose of the current study was to evaluate the effect of captopril on the protective action of numerous antiepileptic drugs (carbamazepine [CBZ], phenytoin [PHT], valproate [VPA], phenobarbital [PB], oxcarbazepine [OXC], lamotrigine [LTG] and topiramate [TPM]) against maximal electroshock-induced seizures in mice. This study was accompanied by an evaluation of adverse effects of combined treatment with captopril and antiepileptic drugs in the passive avoidance task and chimney test. Captopril (25 and 50 mg/kg i.p.) did not influence the threshold for electroconvulsions. Among the tested antiepileptics, captopril (25 and 50 mg/kg i.p.) potentiated the antiseizure action of CBZ, decreasing its ED(50) value from 12.1 to 8.9 and 8.7 mg/kg, respectively. Moreover, captopril (50 mg/kg i.p.) enhanced the anticonvulsant activity of LTG. ED(50) value for LTG was lowered from 5.1 to 3.5 mg/kg. The observed interactions between captopril and CBZ or LTG were pharmacodynamic in nature as captopril did not alter plasma and total brain concentrations of these antiepileptics. The combinations of captopril with antiepileptic drugs did not lead to retention deficits in the passive avoidance task or motor impairment in the chimney test. Based on the current preclinical data, it is suggested that captopril may positively interact with CBZ and LTG in epileptic patients. The combinations of captopril with the remaining antiepileptics (PHT, VPA, PB, OXC and TPM) seem neutral.

Effect of aliskiren on the anticonvulsant activity of antiepileptic drugs against 6 Hz-induced psychomotor seizures in mice.

Drug-drug interactions should be considered during the pharmacological treatment in patients with epilepsy and coexisting hypertension. Experimental studies in rodents showed that antihypertensive drugs which block the renin-angiotensin system (RAS) are able to decrease seizure severity. The anticonvulsant efficacy of several antiepileptic drugs (AEDs) was enhanced in different seizure models following concomitant treatment with RAS inhibitors. The current study examined the combined treatment with AEDs (carbamazepine, valproate, phenobarbital, clonazepam, ethosuximide, levetiracetam) and aliskiren, the first inhibitor of renin for treating hypertension, in the mouse 6 Hz psychomotor seizure model. The convulsive threshold was not affected by the renin inhibitor up to a dose of 75 mg/kg i.p. However, aliskiren (75 mg/kg) enhanced the anticonvulsant action of valproate reducing its ED50 value from 96.7 to 25.6 mg/kg (P < 0.01). The anticonvulsant potency of other AEDs was unaffected by aliskiren treatment. The combinations of aliskiren with AEDs did not cause adverse effects in mice evaluated in the rota-rod or passive avoidance task. Administration of the renin inhibitor did not significantly alter either plasma or brain concentration of valproate. The obtained results confirm earlier findings from other seizure tests (maximal electroshock and pentylenetetrazole-induced seizure test) that aliskiren has a neutral or positive effect on the anticonvulsant efficacy of AEDs, which suggest its safe use for the treatment of high blood pressure in patients with epilepsy. The beneficial anticonvulsant effect of the concomitant treatment with aliskiren and valproate is worthy of recommendation to further both preclinical and clinical studies.

Atherosclerotic risk among children taking antiepileptic drugs.

Epilepsy is a common chronic neurological disorder that requires long-term or sometimes lifetime therapy. Recent evidence indicates that prolonged use of antiepileptic drugs (AEDs) might modify some vascular risk factors; however, the influence of AED therapy on the development of atherosclerosis has been the subject of controversy. Some epidemiological studies have reported a higher prevalence of ischemic vascular disease among epileptic patients on AEDs, while in other studies the mortality due to atherosclerosis-related cardiovascular disease in treated epileptics has been observed to be lower than in the general population. The etiology of atherosclerosis-related vascular diseases in epileptic patients has not been fully clarified. Since atherosclerotic vascular alterations may start early in life, this review focuses on major atherogenic risk factors among epileptic children, including altered metabolism of homocysteine, disordered lipid profiles, and increased lipoprotein (a) serum levels, as well as thyroid hormone deficiency with special concern for clinical implications.

Effect of aliskiren, a direct renin inhibitor, on the protective action of antiepileptic drugs against pentylenetetrazole-induced clonic seizures in mice.

It has been demonstrated that certain angiotensin-converting enzyme (ACE) inhibitors and angiotensin AT1 receptor antagonists can possess anticonvulsant activity. The purpose of the current study was to examine the effect of aliskiren, a direct renin inhibitor and a novel antihypertensive drug, against pentylenetetrazole (PTZ)-induced clonic seizures in mice and on the protective activity of conventional antiepileptic drugs (AEDs) in this seizure model. Effects of aliskiren on the PTZ threshold and the protective efficacy of AEDs, such as clonazepam (CLO), phenobarbital (PB), valproate (VPA), and ethosuximide (ETX) in the PTZ test, were evaluated in adult Swiss mice. Aliskiren and AEDs were administered intraperitoneally (i.p.) while PTZ (50-100 mg/kg) was injected subcutaneously (s.c.). The rota-rod and passive avoidance test were used to assess the adverse effects of the combined treatment with aliskiren and AEDs. Aliskiren, at the dose of 75 mg/kg, significantly raised the PTZ threshold (P < 0.05). Furthermore, aliskiren, at the subthreshold dose of 50 mg/kg, significantly enhanced the protective action of CLO (P < 0.01), PB (P < 0.01), and VPA (P < 0.05) but not ETX (P > 0.05) in the s.c. PTZ test. Motor coordination in the rota-rod test and long-term memory in the passive avoidance task were not impaired by the combined treatment of the drugs. This study suggests that treatment with aliskiren can be useful in hypertensive patients with myoclonic seizures. Certainly, a clinical verification of using aliskiren in such patients would be necessary.

Effects of selective inhibition of N-acetylated-alpha-linked-acidic dipeptidase (NAALADase) on mice in learning and memory tasks.

The purpose of the present study was to examine the effects of 2-(phosphonomethyl)-pentanedioic acid (2-PMPA), a selective inhibitor of N-acetylated-alpha-linked-acidic dipeptidase (NAALADase, glutamate carboxypeptidase II), an enzyme catalyzing the cleavage of glutamate from the neuropeptide N-acetyl-aspartyl-glutamate (NAAG), on memory processes in mice. Long-term memory was evaluated in step-through passive avoidance task while alternation behavior, as a measure involving spatial working memory, was assessed in Y-maze task. Additionally, horizontal activity was evaluated by means of electronically monitored locomotor activity system. The mice were treated with either 2-PMPA (50, 100 and 150 mg/kg i.p.) or N-methyl-d-aspartate (NMDA) receptor antagonist, (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5,10-imine hydrogen maleate (MK-801) at doses of: 0.05, 0.1, 0.15 and 0.2 mg/kg i.p., as a comparator. In the passive avoidance task, the drugs were administered once before or immediately after training, and before retention test. 2-PMPA at the doses used did not affect retention of passive avoidance; however, it increased the latency to enter the dark box during the training day. In the Y-maze task, 2-PMPA (150 mg/kg i.p.) impaired spontaneous alternation and reduced locomotion while the lower dose of 100 mg/kg was ineffective. In the locomotor activity test, 2-PMPA (100 and 150 mg/kg i.p.) did not significantly affect horizontal activity. MK-801 (0.2 mg/kg i.p.) injected before training reduced retention in the passive avoidance task. In the Y-maze task, MK-801 (0.1 mg/kg i.p.) impaired alternation behavior and considerably increased locomotion in the Y-maze and locomotor activity test. These results indicate that NAALADase inhibition may impair alternation behavior.

Interactions of aliskiren, a direct renin inhibitor, with antiepileptic drugs in the test of maximal electroshock in mice.

Experimental studies showed that certain angiotensin-converting enzyme inhibitors and angiotensin AT1 receptor antagonists can decrease seizure severity in rodents. Additionally, some of these blockers of the renin-angiotensin system have been documented to enhance the anticonvulsant activity of antiepileptic drugs against maximal electroshock-induced seizures. The aim of the current study was to investigate the effect of aliskiren, a direct renin inhibitor and a novel antihypertensive drug, on the protective action of numerous antiepileptic drugs (carbamazepine, valproate, clonazepam, phenobarbital, oxcarbazepine, lamotrigine, topiramate and pregabalin) in the test of maximal electroshock in mice. The examined drugs were administered intraperitoneally. Aliskiren up to a dose of 75mg/kg did not affect the threshold for electroconvulsions, however, aliskiren (75mg/kg) enhanced the anticonvulsant action of clonazepam and valproate. Following aliskiren treatment, a higher brain concentration of valproate was noted, suggesting a pharmacokinetic interaction. In the rota-rod test, the concomitant treatment with aliskiren (50 or 75mg/kg) and clonazepam (22.6mg/kg) impaired motor coordination while clonazepam (22.6mg/kg) alone showed strong tendency towards this impairment. The combination of aliskiren (75mg/kg) with phenobarbital (25.5mg/kg) caused long-term memory deficits in the passive avoidance task. This study shows that there are no negative interactions between aliskiren and the examined antiepileptic drugs as concerns their anticonvulsant activity. Aliskiren even potentiated the anticonvulsant action of clonazepam and valproate against maximal electroshock. The impact of aliskiren alone on seizure activity or on the anticonvulsant and adverse activity of antiepileptic drugs needs further evaluation in other animal models of seizures.

Mechanisms of epileptogenesis and preclinical approach to antiepileptogenic therapies.

The prevalence of epilepsy is estimated 5-10 per 1000 population and around 70% of patients with epilepsy can be sufficiently controlled by antiepileptic drugs (AEDs). Epileptogenesis is the process responsible for converting normal into an epileptic brain and mechanisms responsible include among others: inflammation, neurodegeneration, neurogenesis, neural reorganization and plasticity. Some AEDs may be antiepileptiogenic (diazepam, eslicarbazepine) but the correlation between neuroprotection and inhibition of epileptogenesis is not evident. Antiepileptogenic activity has been postulated for mTOR ligands, resveratrol and losartan. So far, clinical evidence gives some hope for levetiracetam as an AED inhibiting epileptogenesis in neurosurgical patients. Biomarkers for epileptogenesis are needed for the proper selection of patients for evaluation of potential antiepileptogenic compounds.

Effect of lead exposure on memory processes in mice after cerebral oligemia.

The purpose of this study was to find out whether the effect of acute exposure to lead on memory processes in mice could be exacerbated by cerebral oligemia. Adult mice were subjected to 30 min of bilateral clamping of carotid arteries (BCCA) and then treated intraperitoneally with lead acetate at a single dose of: 29.3 mg/kg, 58.6 mg/kg or 87.9 mg/kg. Long-term memory was assessed in the passive avoidance task while spontaneous alternation was evaluated using the Y-maze task. Performance of the tasks was tested on the 2nd, 7th and 14th post-surgical day. On the 14th post-surgical day, significant retention deficits in passive avoidance performance were only observed in BCCA mice injected with the 87.9 mg/kg lead. Co-exposure to cerebral oligemia and lead did not change spontaneous alternation in the Y-maze task. These results show that cerebral oligemic hypoxia combined with acute lead exposure may cause selective and long-lasting impairment in memory function.

Cerebral oligemic hypoxia and MK-801 treatment: effect on alternation behavior in mice.

It is known that glutamatergic system is one of neurotransmitter systems affected by a transiently reduced oxygen supply. The aim of the present study was to examine the effects of MK-801, a noncompetitive NMDA receptor antagonist, on spontaneous alternation in mice exposed to cerebral oligemic hypoxia. Spontaneous alternation behavior and locomotor activity were evaluated using the Y-maze task. Transient cerebral oligemia was induced by bilateral clamping of carotid arteries (BCCA) for 30 min under pentobarbital anesthesia. MK-801 was injected 48 h after BCCA or sham surgery, 30 min before the test session. Treatment with MK-801 (0.1 mg/kg ip) impaired spontaneous alternation both in sham-operated and BCCA mice. MK-801 (0.1 mg/kg ip) significantly enhanced the locomotion of mice. The effects of MK-801 were not exacerbated by BCCA. These results show that cerebral oligemic hypoxia induced by BCCA does not change alternation behavior of mice treated with MK-801.