ANTICONVULSANT AND PROCOGNITIVE EFFECT OF NONIMIDAZOLE HISTAMINE H3R RECEPTOR ANTAGONISTS /INVERSE AGONISTS IN EXPERIMENTAL ANIMAL MODELS

Epilepsy is a common chronic neurological disorder accompanied by cognitive impairment. Available antiepileptic drugs (AEDs) have not been reported to have ameliorative effects on epilepsy-associated memory impairment. The potential of histamine H3 receptors (H3R) in several neuropsychiatric diseases, including epilepsy and Alzheimer’s disease, is well recognized. In this study, a series of H3R antagonists (1-16) were screened for their in vivo anticonvulsant effect in several acute-induced seizures in rats. Moreover, the procognitive effect of the most promising H3R antagonist was investigated in dizocilpine (DIZ)-induced amnesic effect applying several behavioral memory tests. Furthermore, the most promising H3R antagonist was assessed for its simultaneous anticonvulsant and procognitive effect and its modulatory effect on levels of oxidative stress markers, several hippocampal neurotransmitters, and c-fos protein expression in the PTZ model. Finally, the promising H3R antagonist was examined for its anticonvulsant effect in PLC-induced SE and its ability to mitigate SE incidence. The Observed results indicated that H3R antagonist 4 (10 mg/kg i.p.) significantly exhibited high protection in maximum electroshock (MES)-induced seizures facilitated through histaminergic neurotransmission and activation of post-synaptically located H1R and full protection in the PTZ-acute induced seizures, Moreover, H3R antagonist 4 (5 mg/kg i.p.) showed a procognitive effect that was abrogated with RAM co-injection in all behavioral memory tests. Additionally, treatment with H3R antagonist 4 showed a simultaneous anticonvulsant and procognitive effect in addition to antioxidant effect in PTZ- acute and -chronic models. Furthermore, chronic treatment with H3R antagonist 4 (5 mg/kg i.p.) modified histamine, acetylcholine, and glutamate release, and reduced hippocampal c-fos activation. In addition, RAMadministration reversed the protective effects provided by H3R antagonist 4 in PTZ chronic model. Moreover, and in PLC-induced SE, systemic administration of H3R antagonist 4 (10 mg/kg i.p.) mitigated the severity of SE and exhibited antioxidant effect in the hippocampus of the treated rats, facilitated through the histaminergic neurotransmission. The observed findings recommend that the newly developed H3R antagonist 4 provides antiepileptic, memory-enhancing, and antioxidant properties in a PTZ-induced kindling model of epilepsy and provides neuroprotection in a preclinical PLC-induced SE in rats, highlighting the histaminergic system as a potential therapeutic target for the management of epilepsy with accompanied memory deficits

The neuroprotective effects of histamine H3 receptor antagonist E177 on pilocarpine-induced status epilepticus in rats

Epilepsy is a multifaceted neurological disorder which severely a ects neuronal function. Some patients may experience status epilepticus (SE), a life-threatening state of ongoing seizure activity linked to cognitive dysfunction, necessitating an immediate intervention. The potential of histamine H3 receptors in several neuropsychiatric diseases including epilepsy is well recognized. In the current study, we aimed to explore the e ect of H3R antagonist E177 on prevention and termination of pilocarpine (PLC)-induced SE in rats as well as evaluating the e ects of E177 on the levels of oxidative stress in hippocampus tissues. The results showed that the survival rate of animals pretreated with E177 (5 and 10 mg/kg, intraperitoneal (i.p.)) was significantly increased during the first hour of observation, and animals were protected from SE incidence and showed a prolonged average of latency to the first seizure when compared with animals pretreated with PLC (400 mg/kg, i.p.). Moreover, the protective e ect of E177 (10 mg/kg) on SE was partially reversed when rats were co- administered with H3R agonist R-( )-methylhistamine (RAM) and with the H2R antagonist zolantidine (ZOL), but not with the H1R antagonist pyrilamine (PYR). Furthermore, pretreatment with E177 (5 and 10 mg/kg) significantly decreased the abnormal levels of malondialdehyde (MDA), and increased levels of glutathione (GSH) in the hippocampal tissues of the treated rats. However, E177 failed to modulate the levels of catalase (CAT), superoxide dismutase (SOD), or acetylcholine esterase activity (AChE). Our findings suggest that the newly developed H3R antagonist E177 provides neuroprotection in a preclinical PLC-induced SE in rats, highlighting the histaminergic system as a potential therapeutic target for the therapeutic management of SE

Antagonism of histamine H3 receptors alleviates pentylenetetrazole-induced kindling and associated memory deficits by mitigating oxidative stress, central neurotransmitters, and c-Fos protein expression in rats

Histamine H3 receptors (H3Rs) are involved in several neuropsychiatric diseases including epilepsy. Therefore, the e ects of H3R antagonist E177 (5 and 10 mg/kg, intraperitoneal (i.p.)) were evaluated on the course of kindling development, kindling-induced memory deficit, oxidative stress levels (glutathione (GSH), malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD)), various brain neurotransmitters (histamine (HA), acetylcholine (ACh), -aminobutyric acid (GABA)), and glutamate (GLU), acetylcholine esterase (AChE) activity, and c-Fos protein expression in pentylenetetrazole (PTZ, 40 mg/kg) kindled rats. E177 (5 and 10 mg/kg, i.p.) significantly decreased seizure score, increased step-through latency (STL) time in inhibitory avoidance paradigm, and decreased transfer latency time (TLT) in elevated plus maze (all P < 0.05). Moreover, E177 mitigated oxidative stress by significantly increasing GSH, CAT, and SOD, and decreasing the abnormal level of MDA (all P < 0.05). Furthermore, E177 attenuated elevated levels of hippocampal AChE, GLU, and c-Fos protein expression, whereas the decreased hippocampal levels of HA and ACh were modulated in PTZ-kindled animals (all P < 0.05). The findings suggest the potential of H3R antagonist E177 as adjuvant to antiepileptic drugs with an added advantage of preventing cognitive impairment, highlighting the H3Rs as a potential target for the therapeutic management of epilepsy with accompanied memory deficits

The Neuroprotective Effects of Histamine H3 Receptor Antagonist E177 on Pilocarpine-Induced Status Epilepticus in Rats

Epilepsy is a multifaceted neurological disorder which severely affects neuronal function. Some patients may experience status epilepticus (SE), a life-threatening state of ongoing seizure activity linked to cognitive dysfunction, necessitating an immediate intervention. The potential of histamine H3 receptors in several neuropsychiatric diseases including epilepsy is well recognized. In the current study, we aimed to explore the effect of H3R antagonist E177 on prevention and termination of pilocarpine (PLC)-induced SE in rats as well as evaluating the effects of E177 on the levels of oxidative stress in hippocampus tissues. The results showed that the survival rate of animals pretreated with E177 (5 and 10 mg/kg, intraperitoneal (i.p.)) was significantly increased during the first hour of observation, and animals were protected from SE incidence and showed a prolonged average of latency to the first seizure when compared with animals pretreated with PLC (400 mg/kg, i.p.). Moreover, the protective effect of E177 (10 mg/kg) on SE was partially reversed when rats were co- administered with H3R agonist R-(&alpha;)-methylhistamine (RAM) and with the H2R antagonist zolantidine (ZOL), but not with the H1R antagonist pyrilamine (PYR). Furthermore, pretreatment with E177 (5 and 10 mg/kg) significantly decreased the abnormal levels of malondialdehyde (MDA), and increased levels of glutathione (GSH) in the hippocampal tissues of the treated rats. However, E177 failed to modulate the levels of catalase (CAT), superoxide dismutase (SOD), or acetylcholine esterase activity (AChE). Our findings suggest that the newly developed H3R antagonist E177 provides neuroprotection in a preclinical PLC-induced SE in rats, highlighting the histaminergic system as a potential therapeutic target for the therapeutic management of SE

Studies on Anticonvulsant Effects of Novel Histamine H3R Antagonists in Electrically and Chemically Induced Seizures in Rats

A newly developed series of non-imidazole histamine H3 receptor (H3R) antagonists (1&#8315;16) was evaluated in vivo for anticonvulsant effects in three different seizure models in Wistar rats. Among the novel H3R antagonists examined, H3R antagonist 4 shortened the duration of tonic hind limb extension (THLE) in a dose-dependent fashion in the maximal electroshock (MES)-induced seizure and offered full protection against pentylenetetrazole (PTZ)-induced generalized tonic-clonic seizure (GTCS), following acute systemic administration (2.5, 5, 10, and 15 mg/kg, i.p.). However, only H3R antagonist 13, without appreciable protective effects in MES- and PTZ-induced seizure, fully protected animals in the strychnine (STR)-induced GTCS following acute systemic pretreatment (10 mg/kg, i.p.). Moreover, the protective effect observed with H3R antagonist 4 in MES-induced seizure was completely abolished when animals were co-administered with the H3R agonist (R)-&#945;-methylhistamine (RAMH, 10 mg/kg, i.p.). However, RAMH failed to abolish the full protection provided by the H3R antagonist 4 in PTZ-induced seizure and H3R antagonist 13 in STR-induced seizure. Furthermore, in vitro antiproliferative effects or possible metabolic interactions could not be observed for compound 4. Additionally, the predictive in silico, as well as in vitro, metabolic stability for the most promising H3R antagonist 4 was assessed. The obtained results show prospective effects of non-imidazole H3R antagonists as innovative antiepileptic drugs (AEDs) for potential single use against epilepsy