Evaluation of the impact of compound C11 a new anticonvulsant candidate on cognitive functions and hippocampal neurogenesis in mouse brain

Andres-Mach, Marta; Szewczyk, Aleksandra; Zagaja, Mirosław; Łuszczki, Jarogniew J.; Maj, Maciej; Rola, Radosław; Abram, Michał; Kamiński, Krzysztof

doi:10.1016/j.neuropharm.2019.107849

Cited by 14 publications

(39 citation statements)

References 69 publications

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“…Evaluation of the potent changes in neurogenesis several weeks after PILO-SE enables a thorough analysis of the newly formed cells in the epileptic brain [37]. Our recent study using the long-term administration of C11 in healthy mice did not indicate any disturbances in the hippocampal neurogenesis, which was also confirmed in the present study [27]. Interestingly, a long-term treatment with C11 of PILO mice significantly increased the total amount of newborn cells, including astrocytes, similarly to the level of the healthy control group.…”

Section: Discussionsupporting

confidence: 90%

“…The results we obtained indicated that hybrid compound C11 used chronically has no negative impact on learning and memory functions in mice. Similarly, the long-term administration of C11 did not cause neuronal degeneration or neurogenesis in treated mice [27].…”

Section: Introductionmentioning

confidence: 82%

“…Taking into consideration the anticonvulsant and neuroprotective activity of LEV in a mouse PILO model of epilepsy [23][24][25], the 6 Hz [26], and anticonvulsant activity of C11 in acute animal models of epilepsy [22], we decided to investigate an impact of the long-term treatment with C11 on neuroprotection, hippocampal neurogenesis, and cognitive functions in mice [27]. The results we obtained indicated that hybrid compound C11 used chronically has no negative impact on learning and memory functions in mice.…”

Section: Introductionmentioning

confidence: 99%

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Preclinical Assessment of a New Hybrid Compound C11 Efficacy on Neurogenesis and Cognitive Functions after Pilocarpine Induced Status Epilepticus in Mice

Andres-Mach

Szewczyk

Zagaja

et al. 2021

IJMS

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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.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

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Preclinical Assessment of a New Hybrid Compound C11 Efficacy on Neurogenesis and Cognitive Functions after Pilocarpine Induced Status Epilepticus in Mice

Andres-Mach

Szewczyk

Zagaja

et al. 2021

IJMS

Self Cite

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“…Interestingly, chronic administration of a new hybrid compound (designated C11) synthesized from the drugs lacosamide, ethosuximide (ETS), and levetiracetam (LEV) suppressed the progression of seizures in the model induced by repeated administrations of PTZ in mice [35]. This compound revealed a broader spectrum of protection by combining anticonvulsant properties of each drug that creates its hybrid structure, demonstrating a likely multidirectional mechanism [36].…”

Section: Discussionmentioning

confidence: 99%

Lacosamide improves biochemical, genotoxic, and mitochondrial parameters after PTZ‐kindling model in mice

Lazzarotto

Pflüger

Regner

et al. 2020

Fundamemntal Clinical Pharma

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This study evaluated the effect of lacosamide (LCM) on biochemical and mitochondrial parameters after PTZ kindling in mice. Male mice were treated on alternative days for a period of 11 days with LCM (20, 30, or 40 mg/kg), saline, or diazepam (2 mg/kg), before PTZ administration (50 mg/kg). The hippocampi were collected to evaluate free radicals, the activities of superoxide dismutase (SOD), catalase (CAT), and the mitochondrial complexes I‐III, II, and II‐III, as well as Bcl‐2 and cyclo‐oxygenase‐2 (COX‐2) expressions. Hippocampi, blood, and bone marrow were collected for genotoxic and mutagenic evaluations. LCM 40 mg/kg increased latency and decreased percentage of seizures, only on the 3rd day of observation. The dose of 30 mg/kg only showed positive effects on the percentage of seizures on the 2nd day of observation. LCM decreased free radicals and SOD activity and the dose of 40 mg/kg were able to increase CAT activity. LCM 30 and 40 mg/kg improved the enzymatic mitochondrial activity of the complex I‐III and LCM 30 mg/kg improved the activity of the complex II. In the comet assay, the damage induced by PTZ administration was reduced by LCM 20 and 30 mg/kg. The dose of 20 mg/kg increased COX‐2 expression while the highest dose used, 40 mg/kg, was able to reduce this expression when compared to the group treated with LCM 20 mg/kg. Although LCM did not produce the antiepileptogenic effect in vivo, it showed the neuroprotective effect against oxidative stress, bioenergetic dysfunction, and DNA damage induced by the repeated PTZ administration.

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“…Combined therapies with cannabinoids and AEDs have been tested to assess the potential benefits of a conjoint treatment. Arachidonyl-2′-chloroethylamide (ACEA) has been tested with the AEDs valproic acid, levetiracetam, ethosuximide, lacosamide, or C11 (a new hybrid compound made from levetiracetam, ethosuximide, and lacosamide) in different models of induced-seizures, and were able to recover proliferation of NSCs and to promote neuronal differentiation [ 262 , 263 , 264 , 265 , 266 , 267 ] ( Figure 5 ). Treatment with WIN 55,212-2 was shown to prevent chronic epileptic hippocampal damage in rat [ 268 , 269 ] and mouse [ 270 , 271 ] models by attenuating the severity and frequency of spontaneous recurrent seizures.…”

Section: Cannabinoids and The Endocannabinoid Systemmentioning

confidence: 99%

Neural Stem Cells and Cannabinoids in the Spotlight as Potential Therapy for Epilepsy

Lourenço

Ribeiro-Rodrigues

Sebastião

et al. 2020

IJMS

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Epilepsy is one of the most common brain diseases worldwide, having a huge burden in society. The main hallmark of epilepsy is the occurrence of spontaneous recurrent seizures, having a tremendous impact on the lives of the patients and of their relatives. Currently, the therapeutic strategies are mostly based on the use of antiepileptic drugs, and because several types of epilepsies are of unknown origin, a high percentage of patients are resistant to the available pharmacotherapy, continuing to experience seizures overtime. Therefore, the search for new drugs and therapeutic targets is highly important. One key aspect to be targeted is the aberrant adult hippocampal neurogenesis (AHN) derived from Neural Stem Cells (NSCs). Indeed, targeting seizure-induced AHN may reduce recurrent seizures and shed some light on the mechanisms of disease. The endocannabinoid system is a known modulator of AHN, and due to the known endogenous antiepileptic properties, it is an interesting candidate for the generation of new antiepileptic drugs. However, further studies and clinical trials are required to investigate the putative mechanisms by which cannabinoids can be used to treat epilepsy. In this manuscript, we will review how cannabinoid-induced modulation of NSCs may promote neural plasticity and whether these drugs can be used as putative antiepileptic treatment.

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Evaluation of the impact of compound C11 a new anticonvulsant candidate on cognitive functions and hippocampal neurogenesis in mouse brain

Cited by 14 publications

References 69 publications

Preclinical Assessment of a New Hybrid Compound C11 Efficacy on Neurogenesis and Cognitive Functions after Pilocarpine Induced Status Epilepticus in Mice

Preclinical Assessment of a New Hybrid Compound C11 Efficacy on Neurogenesis and Cognitive Functions after Pilocarpine Induced Status Epilepticus in Mice

Lacosamide improves biochemical, genotoxic, and mitochondrial parameters after PTZ‐kindling model in mice

Neural Stem Cells and Cannabinoids in the Spotlight as Potential Therapy for Epilepsy

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