Status epilepticus (SE) is a frequent medical emergency that can lead to a variety of neurological disorders, including cognitive impairment and abnormal neurogenesis. The aim of the presented study was the in vitro evaluation of potential neuroprotective properties of a new pyrrolidine-2,5-dione derivatives compound C11, as well as the in vivo assessment of the impact on the neurogenesis and cognitive functions of C11 and levetiracetam (LEV) after pilocarpine (PILO)-induced SE in mice. The in vitro results indicated a protective effect of C11 (500, 1000, and 2500 ng/mL) on astrocytes under trophic stress conditions in the MTT (3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide) test. The results obtained from the in vivo studies, where mice 72 h after PILO SE were treated with C11 (20 mg/kg) and LEV (10 mg/kg), indicated markedly beneficial effects of C11 on the improvement of the neurogenesis compared to the PILO control and PILO LEV mice. Moreover, this beneficial effect was reflected in the Morris Water Maze test evaluating the cognitive functions in mice. The in vitro confirmed protective effect of C11 on astrocytes, as well as the in vivo demonstrated beneficial impact on neurogenesis and cognitive functions, strongly indicate the need for further advanced molecular research on this compound to determine the exact neuroprotective mechanism of action of C11.
Seizures in about 40% of patients with epilepsy fail to respond to anti-seizure medication (ASM) and may lead to uncontrolled and prolonged seizures often inducing status epilepticus (SE). The aim of the study was to evaluate the impact of a long-term treatment with two different generation ASMs: ethosuximide (ETS, a classic ASM) and lacosamide (LCM, a 3rd generation ASM) on neural stem cells’ (NSCs’) proliferation and learning and memory functions after pilocarpine (PILO)-induced SE in mice. The following drugs were used: LCM (10 mg/kg), ETS (20 mg/kg), and PILO (300 mg/kg). Cell counting was done using confocal microscope and ImageJ software. Cognitive functions were evaluated with the Morris water maze (MWM) test. The level of several selected neurometabolites was measured with magnetic resonance spectroscopy (MRS). Obtained results indicated no significant impact of ETS treatment on the neurogenesis process in PILO mice. Interestingly, LCM significantly decreased the total amount of newborn neurons. The MWM test indicated no significant changes in the time and distance traveled by the ETS and LCM groups compared to PILO control mice, although all measured parameters were more favorable for the PILO mice treated with ASM. Conclusions: The presented results show that long term treatment with LCM and ETS seems to be safe for the cognitive functions and the proper course of neurogenesis in the mouse PILO-induced SE model, although one should remember that LCM administered chronically may act to reduce new neurons’ formation.
Xanthotoxin (8‐methoxypsoralen; XANT) is a furanocoumarin that has many biological properties, including antiepileptic activity. This study evaluated the effect of XANT on the ability of classical and novel antiepileptic drugs to prevent seizures evoked by the 6‐Hz corneal stimulation‐induced seizure model, which is thought to be an experimental model of psychomotor (limbic) seizures in humans. XANT (50 mg/kg, administered i.p.) significantly potentiated the anticonvulsant activity of levetiracetam and valproate, decreasing their median effective dose (ED50) values from 19.37 to 2.83 mg/kg (P < 0.01) for levetiracetam and from 92.89 to 44.44 mg/kg (P < 0.05) for valproate. Neither XANT (50 mg/kg) alone nor its combination with the anticonvulsant drugs (at their ED50 values from the 6‐Hz test) affected motor coordination; skeletal muscular strength and long‐term memory, as determined in the chimney; and grip strength and passive avoidance tests, respectively. Measurement of total brain antiepileptic drug concentrations revealed that XANT (50 mg/kg) had no impact on levetiracetam total brain concentrations, indicating the pharmacodynamic nature of interaction between these antiepileptic drugs in the mouse 6‐Hz model. However, XANT (50 mg/kg, i.p.) significantly increased total brain concentrations of valproate (P < 0.01), indicating the pharmacokinetic nature of interactions between drugs. XANT in combination with levetiracetam exerts beneficial anticonvulsant pharmacodynamic interactions in the 6‐Hz mouse psychomotor seizure model.
Epilepsy is a chronic neurological disease characterized by recurrent seizures that affects about 70 million people worldwide.Antiepileptic drugs are the most commonly used medications in the treatment of epilepsy. They help control seizures in about 60-70% of people. The remaining percentage of patients suffer from drug-resistant epilepsy, prompting scientists to look for natural substances that would prevent seizures or support the effects of drugs in add-on therapy while reducing side effects. Currently, there is a lot of emphasis on natural product. Flavonoids are included in this group, and their use in the treatment of epilepsy could support the effect of other drugs. Due to very good results of preclinical studies, flavonoids are a promising candidate for epilepsy related clinical trials related. The article is an overview of literature reports from the past 10 years including mainly in vivo preclinical research on various models of experimental epilepsy with the use of selected flavonoids.
Umbelliferone (7-hydroxycoumarin; UMB) is a coumarin with many biological properties, including antiepileptic activity. This study evaluated the effect of UMB on the ability of classical and novel antiepileptic drugs (e.g., lacosamide (LCM), levetiracetam (LEV), phenobarbital (PB) and valproate (VPA)) to prevent seizures evoked by the 6-Hz corneal-stimulation-induced seizure model. The study also evaluated the influence of this coumarin on the neuroprotective properties of these drugs in two in vitro models of neurodegeneration, including trophic stress and excitotoxicity. The results indicate that UMB (100 mg/kg, i.p.) significantly enhanced the anticonvulsant action of PB (p < 0.01) and VPA (p < 0.05), but not that of LCM orLEV, in the 6-Hz test. Whether alone or in combination with other anticonvulsant drugs (at their ED50 values from the 6-Hz test), UMB (100 mg/kg) did not affect motor coordination; skeletal muscular strength and long-term memory, as determined in the chimney; grip strength; or passive avoidance tests, respectively. Pharmacokinetic characterization revealed that UMB had no impact on total brain concentrations of PB or VPA in mice. The in vitro study indicated that UMB has neuroprotective properties. Administration of UMB (1 µg/mL), together with antiepileptic drugs, mitigated their negative impact on neuronal viability. Under trophic stress (serum deprivation) conditions, UMB enhanced the neurotrophic abilities of all the drugs used. Moreover, this coumarin statistically enhanced the neuroprotective effects of PB (p < 0.05) and VPA (p < 0.001) in the excitotoxicity model of neurodegeneration. The obtained results clearly indicate a positive effect of UMB on the anticonvulsant and neuroprotective properties of the selected drugs.
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