TY - JOUR
T1 - 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
AU - Alachkar, Alaa
AU - Azimullah, Sheikh
AU - Lotfy, Mohamed
AU - Adeghate, Ernest
AU - Ojha, Shreesh K.
AU - Beiram, Rami
AU - Łażewska, Dorota
AU - Kieć-Kononowicz, Katarzyna
AU - Sadek, Bassem
N1 - Funding Information:
Funding: This research was funded by College of Medicine and Health Sciences and the Office of Graduate Studies and Research, United Arab Emirates University (UAEU Program for Advanced Research), grant number 31M310.
Funding Information:
Acknowledgments: The authors thank College of Medicine and Health Sciences and the Office of Graduate Studies and Research, United Arab Emirates University (UAEU Program for Advanced Research) for providing financial support. The authors also acknowledge the partial support of Jagiellonian University statutory funds (N42/DBS/000039) and the support provided by the EU COST Action MuTaLig CA1513 5 to K.K.-K. and D.Ł.
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
PY - 2020
Y1 - 2020
N2 - Histamine H3 receptors (H3Rs) are involved in several neuropsychiatric diseases including epilepsy. Therefore, the effects 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), γ-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.
AB - Histamine H3 receptors (H3Rs) are involved in several neuropsychiatric diseases including epilepsy. Therefore, the effects 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), γ-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.
KW - AChE activity
KW - Antagonist
KW - C-Fos protein expression
KW - Histamine H3 receptor
KW - Memory impairment
KW - Neuroprotection
KW - Oxidative stress
KW - PTZ-kindling
KW - Rats
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U2 - 10.3390/molecules25071575
DO - 10.3390/molecules25071575
M3 - Article
C2 - 32235506
AN - SCOPUS:85082768256
SN - 1420-3049
VL - 25
JO - Molecules
JF - Molecules
IS - 7
M1 - 1575
ER -