Krzysztof Łukawski

Angiotensin AT1 receptor antagonists enhance the anticonvulsant action of valproate in the mouse model of maximal electroshock

Angiotensin AT1 receptor antagonists, drugs affecting the renin-angiotensin system, are commonly used in the treatment of hypertension and congestive heart failure. It is also known that the renin-angiotensin system exists in the brain and therefore it may be involved in the regulation of seizure susceptibility. The aim of the current study was to evaluate the effects of losartan (2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2(1H-tetrazol-5-yl)-biphenil-4-yl)methyl]imidazole) and telmisartan (49-[(1,49-dimethyl-29-propyl[2,69-bi-1H-benzimidazo]-19-yl)methyl]-[1,19-biphenyl]-2-carboxylic acid), the angiotensin AT1 receptor antagonists which are widely used in clinical practice, on the protective action of conventional antiepileptic drugs (carbamazepine, phenytoin, valproate and phenobarbital) against maximal electroshock-induced seizures in mice. Losartan (10, 20 and 50 mg/kgi.p.) and telmisartan (5, 10 and 30 mg/kgi.p.) did not influence the threshold for electroconvulsions. However, both drugs potentiated the anticonvulsant activity of valproate. Losartan (50 mg/kgi.p.) decreased its ED50 value from 249.8 to 194.6 mg/kg while telmisartan (30 mg/kgi.p.) lowered the ED50 value for valproate from 249.8 to 190.6 mg/kg. The antiseizure action of the remaining antiepileptics was not affected by losartan or telmisartan. The observed interactions between tested angiotensin AT1 receptor antagonists and valproate were pharmacodynamic in nature as either losartan or telmisartan did not alter total brain concentrations of valproate. This finding can be important for epileptic patients receiving valproate and also angiotensin AT1 receptor antagonists due to other medical causes.

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.

Chlorpyrifos and Cypermethrin Induce Apoptosis in Human Neuroblastoma Cell Line SH‐SY5Y

Our previous in vivo studies showed that chlorpyrifos (CPF) and cypermethrin (CM) in a mixture dermally administered, strongly inhibited cholinesterase activity in plasma and the brain and were very toxic to the rat central nervous system. In this work, the mechanisms of neurotoxicity have not been elucidated. We used human undifferentiated SH‐SY5Y cells to study mechanisms of pesticide‐induced neuronal cell death. It was found that chlorpyrifos (CPF) and its mixture with cypermethrin (CPF+CM) induced cell death of SH‐SY5Y cells in a dose‐ and time‐dependent manner, as shown by MTT assays. Pesticide‐induced SH‐SY5Y cell death was characterized by concentration‐dependent down‐regulation of Bcl‐2 and Bcl‐xL as well as an increase in the caspase 3 activation. Pan‐caspase inhibitor Q‐VD‐OPh produced a slight but significant reversal effect of pesticide‐induced toxicity indicating that the major caspase pathways are not integral to CPF‐ and CPF+CM‐induced cell death. Furthermore, signal transduction inhibitors PD98059, SL‐327, SB202190, SP600125 and mecamylamine failed to attenuate pesticides effect. Atropine exhibited minimal ability to reverse toxicity. Finally, it was shown that inhibition of TNF‐α by pomalidomide attenuated CPF‐/CPF+CM‐induced apoptosis. Overall, our data suggest that FAS/TNF signalling pathways may participate in CPF and CPF+CM toxicity.

Interactions between angiotensin AT1 receptor antagonists and second-generation antiepileptic drugs in the test of maximal electroshock

The anticonvulsant activity of angiotensin AT1 receptor antagonists, losartan (2‐n‐butyl‐4‐chloro‐5‐hydroxymethyl‐1‐[(2′(1H‐tetrazol‐5‐yl)‐biphenil‐4‐yl)methyl]imidazole) and telmisartan (49‐[(1,49‐dimethyl‐29‐propyl[2,69‐bi‐1H‐benzimidazo]‐19‐yl)methyl]‐[1,19‐biphenyl]‐2‐carboxylic acid), has been reported recently. It is suggested that AT1 receptor antagonists may affect the protective action of antiepileptic drugs. The aim of this study was to determine the influence of losartan and telmisartan on the anticonvulsant activity of some second‐generation antiepileptics (lamotrigine – LTG, oxcarbazepine – OXC, and topiramate – TPM). For this purpose, the maximal electroshock seizure (MES) test in mice was used. Additionally, the drug combinations were checked for adverse effects in the passive avoidance and chimney tests. In the MES test, losartan at the doses of 30 and 50 mg/kg, administered intraperitoneally (i.p.), potentiated the protective action of LTG (P < 0.01). This interaction was not accompanied by a significant change of LTG level either in plasma or in the brain. Telmisartan at the dose of 30 mg/kg i.p. enhanced the anticonvulsant action of TPM (P < 0.01). However, this interaction was pharmacokinetic in nature, as telmisartan significantly increased plasma and total brain concentrations of TPM (P < 0.001). The combinations of AT1 receptor antagonists with antiepileptic drugs did not affect retention in the passive avoidance test or motor coordination in the chimney test. The potentiation of the anticonvulsant action of LTG by losartan probably on account of pharmacodynamic interactions, make this combination important for further experimental and clinical studies. The combination of telmisartan and TPM is less beneficial due to pharmacokinetic interactions.

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 50xa0mg/kg i.p.) did not influence the threshold for electroconvulsions. Among the tested antiepileptics, captopril (25 and 50xa0mg/kg i.p.) potentiated the antiseizure action of CBZ, decreasing its ED50 value from 12.1 to 8.9 and 8.7xa0mg/kg, respectively. Moreover, captopril (50xa0mg/kg i.p.) enhanced the anticonvulsant activity of LTG. ED50 value for LTG was lowered from 5.1 to 3.5xa0mg/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 ACE inhibitors and AT1 receptor antagonists on pentylenetetrazole-induced convulsions in mice

Experimental data show that some angiotensin-converting enzyme (ACE) inhibitors and angiotensin AT1 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 AT1 antagonists (losartan, telmisartan and candesartan) were examined against pentylenetetrazole (PTZ)-induced seizures in mice. Captopril (50xa0mg/kg) administered intraperitoneally significantly raised the PTZ threshold (pxa0<xa00.05). 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.

Combined treatment with gabapentin and drugs affecting the renin-angiotensin system against electroconvulsions in mice.

Recent experimental data suggest that certain angiotensin-converting enzyme (ACE) inhibitors and angiotensin AT1 receptor antagonists may possess anticonvulsant activity. The purpose of this study was to examine the effects of two ACE inhibitors, captopril and enalapril, and two AT1 receptor antagonists, losartan and telmisartan, on the protective action of gabapentin in the maximal electroshock seizure threshold test in mice. Additionally, the effects of the combined treatment with gabapentin and antihypertensive drugs on memory retention in the passive avoidance task and motor coordination in the chimney test were assessed. All drugs were injected intraperitoneally. Losartan (50mg/kg) significantly increased the convulsive threshold for gabapentin. The other antihypertensive drugs, captopril (50mg/kg), enalapril (30 mg/kg) and telmisartan (30 mg/kg), did not affect the anticonvulsant activity of gabapentin. The observed interaction between gabapentin and losartan could be pharmacokinetic in nature. Losartan increased plasma and total brain concentrations of gabapentin. In the chimney test, losartan (50mg/kg) administered with gabapentin (50mg/kg) caused motor impairment. In the passive avoidance test, memory retention was not affected by the combined treatment with gabapentin and antihypertensive drugs. It is suggested that the use of captopril, enalapril and telmisartan in epileptic patients receiving gabapentin is presumed neutral upon its anticonvulsant action. The utmost caution is advised when combining losartan and gabapentin in clinical practice due to the appearance of pharmacokinetic interactions between losartan and gabapentin as well as motor impairment evoked by these drugs in mice.

Exploring the latest avenues for antiepileptic drug discovery and development

ABSTRACT Introduction: In about 30% of patients with epilepsy, seizures are not sufficiently controlled with the available antiepileptic medication. There is a need for newer drugs, not only aimed at suppressing seizure activity but for the efficient inhibition of epileptogenesis. Areas covered: In this review, the authors consider different approaches for the management of drug-resistant epilepsy and various possible ways on how to stop epileptogenesis. Expert opinion: There is limited evidence for antiepileptogenic effects of antiepileptic drugs. Post-status epilepticus animal models will probably help the discovery of antiepileptogenic compounds among already approved non-antiepileptic drugs or other agents. A good example is losartan, which significantly inhibits epileptogenesis in vivo. Some agents that affect the mTOR signaling system, or that inhibit the synthesis of the proconvulsant cytokine as well as those derived from plants (resveratrol) also seem effective in this regard. Furthermore, agonists of peroxisome proliferator-activated receptors have proven effective in some models of seizures but data on their possible antiepileptogenic activity is quite limited. In addition to the discovery of new antiepileptogenic and/or antiepileptic compounds, there is a possibility of improving the treatment of drug-resistant cases through the rational use of antiepileptic drug combinations.

Interactions between ACE inhibitors and classical antiepileptic drugs in the mouse maximal electroshock seizures.

This study evaluated the effect of two angiotensin-converting enzyme (ACE) inhibitors, enalapril and cilazapril, commonly used antihypertensive drugs, on the protective efficacy of the classical antiepileptics - carbamazepine (CBZ), phenytoin (PHT), valproate (VPA) and phenobarbital (PB). For this purpose, we used the maximal electroshock seizure (MES) test in mice. Additionally, adverse effects of combined treatment with ACE inhibitors and antiepileptic drugs in the passive avoidance task and chimney test were assessed. All drugs were administered intraperitoneally. Neither enalapril (10, 20 and 30 mg/kg) nor cilazapril (5, 10 and 20mg/kg) affected the threshold for electroconvulsions. Enalapril (30 mg/kg) but not cilazapril (20mg/kg), enhanced the protective action of VPA, decreasing its ED(50) value from 249.5 to 164.9 mg/kg (p<0.01). Free plasma (non-protein-bound) and total brain concentrations of VPA were not significantly influenced by enalapril. Therefore, the observed interaction could be pharmacodynamic in nature. The combinations of ACE inhibitors with other antiepileptics (CBZ, PHT, and PB) were ineffective in that their ED(50) values against MES were not significantly changed. Enalapril and cilazapril remained ineffective as regards memory retention in the passive avoidance task or motor performance in the chimney test. The current study suggests that there are no negative interactions between the studied ACE inhibitors and classical antiepileptic drugs. Enalapril was even documented to enhance the anticonvulsant activity of VPA.

Effect of ethacrynic acid on the anticonvulsant activity of the second-generation antiepileptics against maximal electroshock-induced seizures in mice

Recent experimental studies show that ethacrynic acid (ETA), a loop diuretic, exerts the anticonvulsant activity. Therefore, we tested the effect of ETA on the protective action of some second-generation antiepileptic drugs (oxcarbazepine [OXC], lamotrigine [LTG] and topiramate [TPM]) in the mouse maximal electroshock seizure (MES) model. ETA was administered acutely (50 and 100 mg/kg i.p.) or chronically, for 7 days (12.5 mg/kg i.p.). Both ETA acute (up to 100 mg/kg) and chronic (up to 12.5 mg/kg) treatment did not influence the threshold for electroconvulsions. In the MES test, ETA (100 mg/kg) potentiated the protective activity of TPM, decreasing its ED(50) value from 38.1 to 18.7 mg/kg (P<0.01). In contrast, ETA (100 mg/kg) remained without effect on the anticonvulsant action of the other antiepileptics (OXC and LTG) in mice. Chronic administration of ETA (12.5 mg/kg) did not affect the protective action of tested antiepileptics. The observed interaction between acute ETA and TPM was pharmacodynamic in nature because neither plasma nor total brain TPM concentrations were altered after injection of ETA.These results indicate existing interactions between ETA and TPM, which may have some clinical importance for epileptic patients treated with TPM and additionally ETA due to other medical causes.