Anticonvulsant Activity of PNU‐151774E¹ in the Amygdala Kindled Model of Complex Partial Seizures

Abstract

Summary:Purpose: PNU-15 1774E [(S)-(+)-2-(4-(3-fluorobenzyloxy) benzylamino) propanamide, methanesulfonate] is a novel antiepileptic drug (AED) with a broad spectrum of activity in a variety of chemically and mechanically induced seizures. The objective of this study was to evaluate the activity of PNU-151774E in the amygdala fully kindled rat model of complex partial seizures, and to compare its effects with those of carbarnazepine (CBZ), phenytoin (PHT), lamotrigine (LTG), and gabapentin (GBP), drugs used to treat this disease state.Methods: Male Wistar rats were stimulated daily through electrodes implanted in the amygdala with a threshold current until fully generalized seizures developed. The rats were then treated with various doses of a single compound. Control values for each rat and drug dose were determined after vehicle administration followed by electrical stimulation 1 day before drug treatment.Results: PNU-15 1774E (1, 10, 30 mg/kg; i.p.) reduced the duration of behavioral seizures significantly and dosedependently at doses starting from 1 mgkg. Higher doses significantly reduced seizure severity and afterdischarge duration. In contrast, no dose-related effects were noted after administration of PHT, whereas after CBZ treatment, a plateau of activity was noted from the intermediate to higher doses. The effects of PNU-151774E were comparable to those of LTG and GBP.Conclusions: The activity shown by PNU-15 1774E at doses similar to those that are active in models of generalized seizures indicates that PNU-15 1774E would also have potential efficacy in the treatment of complex partial seizures.

Differential distribution of voltage‐gated calcium channel alpha‐2 delta (α2δ) subunit mRNA‐containing cells in the rat central nervous system and the dorsal root ganglia

“…Although neuronal activity in the hippocampus, mediated by VGCCs containing the α 2 δ‐1 subunit, may play an important role in learning and memory in the normal physiological state, abnormal firing, due to brain trauma, infection, or tumor, of neurons in the hippocampus, cortex, or amygdala has been found to be attributable to the onset of seizures (Nestler,2001; McIntyre et al,2002). Thus, consistent with our results, gabapentin and its analogs, which specifically bind to α 2 δ‐1 (Gee et al,1996) and are thought to reduce calcium currents (Stefani et al,1998; Calabresi et al,1999; Fink et al,2000), are efficacious against focal epilepsy in adult humans and in animal models of focal seizures (Dalby and Nielsen,1997; Maj et al,1999; Lado et al,2001). Also consistent with our results, radiolabeled gabapentin binds heavily to the rat cortex, the hippocampus, and the amygdala in rats (Gu et al, unpubl.…”

Evaluation of antiseizure drug efficacy and tolerability in the rat lamotrigine‐resistant amygdala kindling model

“…Further, resistance in patients is not due to treatment with any particular drug or drug class. 50,51 This suggests that, as in human epilepsy populations, drug tolerance in this model occurs for multiple ASDs. We observed that in addition to sodium channel blockers, compounds acting through other mechanisms were also ineffective in this model as compared to amygdala kindling alone.…”

Merging Structural Motifs of Functionalized Amino Acids and α-Aminoamides Results in Novel Anticonvulsant Compounds with Significant Effects on Slow and Fast Inactivation of Voltage-Gated Sodium Channels and in the Treatment of Neuropathic Pain

“…Pharmacologically, ( R )- 4 , ( S )- 5 , and ( S )- 6 exhibited excellent seizure protection 10,19,20 in the maximal electroshock seizure (MES) animal model, 21 and electrophysiology studies demonstrated that these agents modulated sodium currents. 13,15,22,23 However, ( R )- 4 selectively enhanced the slow-inactivation state of the voltage-gated sodium channel (VGSC), 22,23 while ( S )- 5 inhibited tetrodotoxin-sensitive (TTX-S) fast sodium currents, 13,24 and ( S )- 6 modulated both sodium channel fast and slow inactivation processes.…”