. 2024 Dec 11;46(12):14010-14032.

doi: 10.3390/cimb46120838.

BDNF/Cyclin D1 Signaling System and Cognitive Performance After Perampanel and Lacosamide Treatment Singly or in Combination in an Experimental Model of Temporal Lobe Epilepsy

Michaela Shishmanova-Doseva^{1

2}, Darina Barbutska³

Affiliations

¹ Department of Pharmacology, Toxicology and Pharmacotherapy, Pharmacy Faculty, Medical University Plovdiv, 4002 Plovdiv, Bulgaria.
² Research Institute, Medical University Plovdiv, 4002 Plovdiv, Bulgaria.
³ Department of Anatomy, Histology and Embryology, Medical Faculty, Medical University Plovdiv, 4002 Plovdiv, Bulgaria.

PMID: 39727966
PMCID: PMC11727337
DOI: 10.3390/cimb46120838

BDNF/Cyclin D1 Signaling System and Cognitive Performance After Perampanel and Lacosamide Treatment Singly or in Combination in an Experimental Model of Temporal Lobe Epilepsy

Michaela Shishmanova-Doseva et al. Curr Issues Mol Biol. 2024.

. 2024 Dec 11;46(12):14010-14032.

doi: 10.3390/cimb46120838.

Authors

Michaela Shishmanova-Doseva^{1

2}, Darina Barbutska³

Affiliations

¹ Department of Pharmacology, Toxicology and Pharmacotherapy, Pharmacy Faculty, Medical University Plovdiv, 4002 Plovdiv, Bulgaria.
² Research Institute, Medical University Plovdiv, 4002 Plovdiv, Bulgaria.
³ Department of Anatomy, Histology and Embryology, Medical Faculty, Medical University Plovdiv, 4002 Plovdiv, Bulgaria.

PMID: 39727966
PMCID: PMC11727337
DOI: 10.3390/cimb46120838

Abstract

Epilepsy is a common brain function disorder. The present study aims to evaluate the long-term effect of perampanel (PRM) and lacosamide (LCM), administered singly in a high-dose or in a low-dose combination of both, on comorbid anxiety, cognitive impairment, BDNF, and Cyclin D1 hippocampal expression in an experimental model of temporal lobe epilepsy with lithium-pilocarpine. PRM (3 mg/kg, p.o.)/LCM (30 mg/kg, p.o.) or PRM+LCM (0.5 mg/kg + 3 mg/kg, p.o.) treatments were administered three hours after the lithium-pilocarpine-induced status epilepticus and continued for up to ten weeks in adult Wistar rats. Our study demonstrated that perampanel and lacosamide administered singly in high doses improved epilepsy-associated cognitive impairment through ameliorating anxiety and facilitating passive learning and memory, with spatial and recognition memory measured in the elevated plus maze, step-through, Y-maze, and object recognition tests, respectively. In addition, the combination of both drugs in low doses demonstrated similar anxiolytic and cognitive-improving effects compared to the singly administered drugs. Moreover, the three experimental groups enhanced the hippocampal expression of the neurotrophic factor BDNF and mitigated the increased levels of the apoptotic factor Cyclin D1. These beneficial effects could be essential mechanisms through which administered anticonvulsants preserve neuronal survival and homeostasis in the CNS and especially in the hippocampus.

Keywords: BDNF; apoptosis; cyclin D1; hippocampus; lacosamide; lithium–pilocarpine; perampanel.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

**Figure 1**
Timeline of the experiment.

**Figure 2**
Effect of long-term treatment with perampanel (PRM) and lacosamide (LCM), singly or in combination, on the discrimination index in the object recognition test in animals with a model of temporal lobe epilepsy. ^{^^} p < 0.01 Li-Pilo-veh group vs. C-veh group; ^{^} p < 0.05 Li-Pilo-PRM vs. C-veh group, * p < 0.05 Li-Pilo-LCM vs. Li-Pilo-veh group; *** p < 0.001 Li-Pilo-PRM-LCM vs. Li-Pilo-veh group; ^# p < 0.05 Li-Pilo-PRM-LCM vs. Li-Pilo-PRM group; no significance (N.S.), p > 0.05 Li-Pilo-LCM vs. Li-Pilo-PRM-LCM group.

**Figure 3**
Effect of long-term treatment with perampanel (PRM) and lacosamide (LCM), singly or in combination, on the spontaneous alternations (%) in the Y-maze test in animals with a model of temporal lobe epilepsy. ^{^^^} p < 0.001 Li-Pilo-veh vs. C-veh group; *** p < 0.001 Li-Pilo-PRM vs. Li-Pilo-veh group; *** p < 0.001 Li-Pilo-LCM vs. Li-Pilo-veh group; * p < 0.05 Li-Pilo-PRM-LCM vs. Li-Pilo-veh group; no significance (N.S.), p > 0.05 C-veh group vs. Li-Pilo-PRM group; p > 0.05 C-veh group vs. Li-Pilo-LCM group; p > 0.05 C-veh group vs. Li-Pilo-PRM-LCM group; N.S., p > 0.05 Li-Pilo-PRM vs. Li-Pilo-PRM-LCM group; N.S., p > 0.05 Li-Pilo-LCM group vs. Li-Pilo-PRM-LCM group.

**Figure 4**
(A). Effect of long-term treatment with perampanel (PRM) and lacosamide (LCM), singly or in combination, on the latency time (s) during a learning session in the step-through passive avoidance test in animals with a model of temporal lobe epilepsy. ^{^} p < 0.05 Li-Pilo-veh vs. C-veh group; *** p < 0.001 Li-Pilo-PRM vs. Li-Pilo-veh group; * p < 0.05 Li-Pilo-LCM vs. Li-Pilo-veh group; *** p < 0.001 Li-Pilo-PRM vs. Li-Pilo-veh group; no significance (N.S.), p > 0.05 C-veh group vs. Li-Pilo-PRM group; p > 0.05 C-veh group vs. Li-Pilo-LCM group; p > 0.05 C-veh group vs. Li-Pilo-PRM-LCM group; N.S., p > 0.05 Li-Pilo-PRM vs. Li-Pilo-PRM-LCM group; N.S., p > 0.05 Li-Pilo-LCM group vs. Li-Pilo-PRM-LCM group. (B). Effect of long-term treatment with perampanel (PRM) and lacosamide (LCM), singly or in combination, on the latency time (s) during a memory retention test in the step-through passive avoidance test in animals with a model of temporal lobe epilepsy. ^{^} p < 0.05 Li-Pilo-veh vs. C-veh group; * p < 0.001 Li-Pilo-PRM vs. Li-Pilo-veh group; *** p < 0.001 Li-Pilo-LCM vs. Li-Pilo-veh group; *** p < 0.001 Li-Pilo-PRM-LCM vs. Li-Pilo-veh group; no significance (N.S.), p > 0.05 C-veh group vs. Li-Pilo-PRM group; p > 0.05 C-veh group vs. Li-Pilo-LCM group; p > 0.05 C-veh group vs. Li-Pilo-PRM-LCM group; N.S., p > 0.05 Li-Pilo-PRM vs. Li-Pilo-PRM-LCM group; N.S., p > 0.05 Li-Pilo-LCM group vs. Li-Pilo-PRM-LCM group.

**Figure 5**
Effect of long-term treatment with perampanel (PRM) and lacosamide (LCM), singly or in combination, on the number of entries in open arms in the elevated plus maze test in animals with a model of temporal lobe epilepsy. ^{^^^} p < 0.001 Li-Pilo-veh vs. C-veh group; *** p < 0.001 Li-Pilo-PRM vs. Li-Pilo-veh group; *** p < 0.001 Li-Pilo-LCM vs. Li-Pilo-veh group; ** p < 0.01 Li-Pilo-PRM-LCM vs. Li-Pilo-veh group; no significance (N.S.), p > 0.05 C-veh group vs. Li-Pilo-PRM group; p > 0.05 C-veh group vs. Li-Pilo-LCM group; p > 0.05 C-veh group vs. Li-Pilo-PRM-LCM group; p > 0.05 Li-Pilo-PRM vs. Li-Pilo-PRM-LCM group; p > 0.05 Li-Pilo-LCM group vs. Li-Pilo-PRM-LCM group.

**Figure 6**
Effect of long-term treatment with perampanel (PRM) and lacosamide (LCM), singly or in combination, on the time (s) spent in open arms in the elevated plus maze test (300 s total time) in animals with a model of temporal lobe epilepsy. ^{^} p < 0.05 Li-Pilo-veh vs. C-veh group; ** p < 0.01 Li-Pilo-LCM vs. Li-Pilo-veh group; no significance (N.S.), p > 0.05 C-veh group vs. Li-Pilo-PRM group; p > 0.05 C-veh group vs. Li-Pilo-LCM group; p > 0.05 C-veh group vs. Li-Pilo-PRM-LCM group; p > 0.05 Li-Pilo-PRM vs. Li-Pilo-PRM-LCM group; p > 0.05 Li-Pilo-LCM group vs. Li-Pilo-PRM-LCM group.

**Figure 7**
Effect of long-term treatment with perampanel (PRM) and lacosamide (LCM), singly or in combination, on the anxiety index in the elevated plus maze test in animals with a model of temporal lobe epilepsy. ^{^^^} p < 0.001 Li-Pilo-veh vs. C-veh group; *** p < 0.001 Li-Pilo-PRM vs. Li-Pilo-veh group; *** p < 0.001 Li-Pilo-LCM vs. Li-Pilo-veh group; *** p < 0.001 Li-Pilo-PRM-LCM vs. Li-Pilo-veh group; no significance (N.S.), p > 0.05 C-veh group vs. Li-Pilo-PRM group; p > 0.05 C-veh group vs. Li-Pilo-LCM group; p > 0.05 C-veh group vs. Li-Pilo-PRM-LCM group; p > 0.05 Li-Pilo-PRM vs. Li-Pilo-PRM-LCM group; p > 0.05 Li-Pilo-LCM group vs. Li-Pilo-PRM-LCM group.

**Figure 8**
Immunohistochemical expression of BDNF in the dorsal hippocampus. C-veh group (A1–A5), Li-Pilo-veh group (B1–B5), Li-Pilo-PRM group (C1–C5), Li-Pilo-LCM group (D1–D5), Li-Pilo-PRM-LCM group (E1–E5). Higher magnifications of the rectangles in all five groups are given. Scale bars = 200 µm (A1,B1,C1,D1,E1); 50 µm (A2–A5,B2–B5,C2–C5,D2–D5,E2–E5).

**Figure 9**
Effect of long-term treatment with perampanel (PRM) and lacosamide (LCM), singly or in combination, on the BDNF levels (RU) in animals with a model of temporal lobe epilepsy: (A) in the hippocampal CA1 subfield, ^{^} p < 0.05, Li-Pilo-veh vs. C-veh group; *** p < 0.001 Li-Pilo-PRM vs. Li-Pilo-veh group; *** p < 0.001 Li-Pilo-LCM vs. Li-Pilo-veh group; *** p < 0.001 Li-Pilo-PRM-LCM vs. Li-Pilo-veh group; no significance (N.S.), p > 0.05 C-veh group vs. Li-Pilo-PRM group; p > 0.05 C-veh group vs. Li-Pilo-LCM group; p > 0.05 C-veh group vs. Li-Pilo-PRM-LCM group; p > 0.05 Li-Pilo-PRM vs. Li-Pilo-PRM-LCM group; p > 0.05 Li-Pilo-LCM group vs. Li-Pilo-PRM-LCM group. (B) in the hippocampal CA2 subfield, ^{^} p < 0.05, Li-Pilo-veh vs. C-veh group; ** p < 0.01 Li-Pilo-PRM vs. Li-Pilo-veh group; * p < 0.05 Li-Pilo-LCM vs. Li-Pilo-veh group; ** p < 0.01 Li-Pilo-PRM-LCM vs. Li-Pilo-veh group; no significance (N.S.), p > 0.05 C-veh group vs. Li-Pilo-PRM group; p > 0.05 C-veh group vs. Li-Pilo-LCM group; p > 0.05 C-veh group vs. Li-Pilo-PRM-LCM group; p > 0.05 Li-Pilo-PRM vs. Li-Pilo-PRM-LCM group; p > 0.05 Li-Pilo-LCM group vs. Li-Pilo-PRM-LCM group; (C) in the hippocampal CA3 subfield, ^{^^^} p < 0.001, Li-Pilo-veh vs. C-veh group; *** p < 0.001 Li-Pilo-PRM vs. Li-Pilo-veh group; *** p < 0.001 Li-Pilo-LCM vs. Li-Pilo-veh group; *** p < 0.001 Li-Pilo-PRM-LCM vs. Li-Pilo-veh group; no significance (N.S.), p > 0.05 C-veh group vs. Li-Pilo-PRM group; p > 0.05 C-veh group vs. Li-Pilo-LCM group; p > 0.05 C-veh group vs. Li-Pilo-PRM-LCM group; p > 0.05 Li-Pilo-PRM vs. Li-Pilo-PRM-LCM group; p > 0.05 Li-Pilo-LCM group vs. Li-Pilo-PRM-LCM group and (D) in the granular cell layer in the dentate gyrus, ^{^^} p < 0.01, Li-Pilo-veh vs. C-veh group; *** p < 0.001 Li-Pilo-PRM vs. Li-Pilo-veh group; *** p < 0.001 Li-Pilo-LCM vs. Li-Pilo-veh group; *** p < 0.001 Li-Pilo-PRM-LCM vs. Li-Pilo-veh group; ^{^} p < 0.05 Li-Pilo-PRM-LCM vs. C-veh group; no significance (N.S.), p > 0.05 C-veh group vs. Li-Pilo-PRM group; p > 0.05 C-veh group vs. Li-Pilo-LCM group; p > 0.05 Li-Pilo-PRM vs. Li-Pilo-PRM-LCM group; p > 0.05 Li-Pilo-LCM group vs. Li-Pilo-PRM-LCM group.

**Figure 10**
(A–E). Immunohistochemical expression of Cyclin D1 in the dorsal hippocampus. C-veh group (A1–A5), Li-Pilo-veh group (B1–B5), Li-Pilo-PRM group (C1–C5), Li-Pilo-LCM group (D1–D5), Li-Pilo-PRM-LCM group (E1–E5). Higher magnifications of the rectangles in all five groups are given. Scale bars = 200 µm (A1,B1,C1,D1,E1); 50 µm (A2–A5,B2–B5,C2–C5,D2–D5,E2–E5).

**Figure 11**
Effect of long-term treatment with perampanel (PRM) and lacosamide (LCM), singly or in combination, on the Cyclin D1 levels (RU) in (A) the hippocampal CA1 subfield, ^{^^^} p < 0.001 Li-Pilo-veh vs. C-veh group, ^{^^} p < 0.01 Li-Pilo-PRM vs. C-veh group, *** p < 0.001 Li-Pilo-PRM vs. Li-Pilo-veh group; *** p < 0.001 Li-Pilo-LCM vs. Li-Pilo-veh group; ^{^^^} p < 0.001 Li-Pilo-PRM-LCM vs. C-veh group, *** p < 0.001 Li-Pilo-PRM-LCM vs. Li-Pilo-veh group; no significance (N.S.), p > 0.05 C-veh group vs. Li-Pilo-LCM group, p > 0.05 Li-Pilo-PRM vs. Li-Pilo-PRM-LCM group; p > 0.05 Li-Pilo-LCM group vs. Li-Pilo-PRM-LCM group (B) CA2 subfield, ^{^^^} p < 0.001 Li-Pilo-veh vs. C-veh group, * p < 0.05 Li-Pilo-PRM vs. Li-Pilo-veh group; * p < 0.05 Li-Pilo-LCM vs. Li-Pilo-veh group; N.S., p > 0.05 C-veh group vs. Li-Pilo-PRM group; p > 0.05 C-veh group vs. Li-Pilo-LCM group; p > 0.05 C-veh group vs. Li-Pilo-PRM-LCM group; p > 0.05 Li-Pilo-PRM vs. Li-Pilo-PRM-LCM group; p > 0.05 Li-Pilo-LCM group vs. Li-Pilo-PRM-LCM group; p > 0.05 Li-Pilo-PRM-LCM vs. Li-Pilo-veh (C) CA3 subfield, ^{^^^} p < 0.001 Li-Pilo-veh vs. C-veh group; ^{^^^} p < 0.01 Li-Pilo-PRM vs. C-veh group; ^{^} p < 0.05, ^{^^} p < 0.01 Li-Pilo-LCM vs. C-veh group; ^{^} p < 0.05, ^{^^^} p < 0.001 Li-Pilo-PRM-LCM vs. C-veh group, *** p < 0.001 Li-Pilo-PRM vs. Li-Pilo-veh group; ^{^} p < 0.05, Li-Pilo-LCM vs. C-veh group; *** p < 0.001 Li-Pilo-LCM vs. Li-Pilo-veh group; ^{^} p < 0.05 Li-Pilo-PRM-LCM vs. C-veh group; *** p < 0.001 Li-Pilo-PRM-LCM vs. Li-Pilo-veh group and (D) in the granular cell layer in the dentate gyrus, ^{^^^} p < 0.001 Li-Pilo-veh vs. C-veh group; ^{^^^} p < 0.001 Li-Pilo-PRM vs. C-veh group; *** p < 0.001 Li-Pilo-PRM vs. Li-Pilo-veh group; ^{^^} p < 0.01 Li-Pilo-LCM vs. C-veh group; *** p < 0.001 Li-Pilo-LCM vs. Li-Pilo-veh group; ^{^^^} p < 0.001 Li-Pilo-PRM-LCM vs. C-veh group; *** p < 0.001 Li-Pilo-PRM-LCM vs. Li-Pilo-veh group.

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BDNF/Cyclin D1 Signaling System and Cognitive Performance After Perampanel and Lacosamide Treatment Singly or in Combination in an Experimental Model of Temporal Lobe Epilepsy

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BDNF/Cyclin D1 Signaling System and Cognitive Performance After Perampanel and Lacosamide Treatment Singly or in Combination in an Experimental Model of Temporal Lobe Epilepsy

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