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

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

Isolation and Identification of Bioactive Secondary Metabolites

The health benefits of food, plants, fruits, and seaweeds stem from the biological activities of their constituents—namely, secondary metabolites. The study of secondary metabolites and their potential to treat and/or prevent a number of diseases has become a research topic of growing interest for biologists, pharmacists, and chemists. Notably, in order to propose a compound as a potential new drug with pharmacological effects, the chemical structure of this compound and its biological activity against a given target must be well established. The Special Issue, “Isolation and Identification of Bioactive Secondary Metabolites”, considers species beyond their nutritional value and identifies instances of wider and more efficient use, thereby contributing to a more sustainable management of natural resources. The fifteen articles published in this Special Issue reflect the latest research trends, and consider the isolation, identification, and assessment of the beneficial effects of secondary metabolites from both edible and inedible species. Thus, these contributions collectively demonstrate that these compounds, and their plants of origin, should be valued beyond their nutritional benefits