GPR40 modulates epileptic seizure and NMDA receptor function

Yang, Yong; Tian, Xin; Xu, Dan; Zheng, Fangshuo; Lu, Xi; Zhang, Yanke; Ma, Yuanlin; Li, Yun; Xu, Xin; Zhu, Binglin; Wang, Xuefeng

doi:10.1126/sciadv.aau2357

Cited by 54 publications

(49 citation statements)

References 52 publications

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“…23 Researchers also reported that enhanced level of intracellular Ca 2+ as a result from activation of inotropic glutamate receptors during abnormal neuronal excitations leads to uncontrolled production of reactive oxygen species (ROS). 24 Along with these findings in current research, PTZ administration disturbed oxidative status in the brain tissue of mice. This subject was supported by elevated concentration of MDA and diminished level of total thiol group as well as reduction of SOD and CAT activity in cortical and hippocampus of PTZ group compared to control group.…”

Section: Discussionsupporting

confidence: 75%

Effect of Captopril on Brain Oxidative Damage in Pentylenetetrazole-Induced Seizures in Mice<br />

et al. 2019

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IntroductionEpileptic seizures are considered as a sever abnormal activity of neurons in specific areas of brain such as temporal lobe. 1 This abnormal activity of neurons can be followed by brain oxidative stress and disturbance of cognitive behaviors when they take place repeatedly. 2 In the epileptic seizure models, antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase have been also shown to protect the brain of rats against oxidative damage. 3 In large number of animal studies, pentylenetetrazole (PTZ) has been repeatedly administered for induction an epilepsy model. 1 It has been ducumented that PTZstimulated seizures was accompanied with motor activity impairment, learning and memory dysfunction, axiety and increased level of hippocampal inflammatory cytokines in rats. 4 In addition, seizures followed by PTZ administration have been propounded as an important cause of oxidative status imbalance in some brain areas including hippocampus. 5 For example, PTZ infusion associated with the sever stimulation of N-Methyl-Daspartate (NMDA) receptors has been shown to elevate the level of free radicals such as nitric oxide (NO) and peroxynitrite in the brain of rats. 6 On the other hand, the antioxidant properties of angiotensin-converting enzyme (ACE) inhibitors have been accepted. 7 Captopril as a known ACE inhibitor scavenges free radicals in various tissues. 8 Captopril has been demonstrated to reinforce enzymatic and nonenzymatic defense in different tissues. 9 Scientific evidence has indicated that captopril and valsartan (a specific AT1 receptor inhibitor) attenuate A B S T R A C TBackground: Frequent seizure is followed by overproduction of free radicals and brain oxidative stress. Renin angiotensin system (RAS) has some effects on central nervous system. We designed this research to challenge the effect of captopril as an angiotensin converting enzyme (ACE) inhibitor against brain oxidative stress in pentylenetetrazole (PTZ) -induced seizures in mice. Methods: The groups were including (1) Control (saline); (2) PTZ (100 mg/kg, i.p.), (3-5) PTZ-captopril (Capto) that received three doses of Capto 10, 50 and 100 mg/kg 30 min before PTZ injection. Latency time in the onset minimal clonic seizures (MCS) and generalized tonic-clonic seizures (GTCS) were recorded. The level of malondialdehyde (MDA) and total thiol, as well as superoxide dismutase (SOD) and catalase (CAT) activity in the hippocampus and cortex were measured. Results: All doses of captopril postponed the onset of MCS and GTCS. Accumulation of MDA in the brain tissues of PTZ group was higher than control group, while total thiol content and CAT activity were lower. Pretreatment with captopril (100 mg/kg) diminished MDA concentration compared with PTZ group. Captopril (50 and 100 mg/kg) also increased the level of total thiol groups versus PTZ group. Captopril injection (50 and 100 mg/kg) elevated the activity of SOD and CAT in the brain tissues. In addition captopril administration diminished mortality rat...

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Section: Discussionsupporting

confidence: 75%

Effect of Captopril on Brain Oxidative Damage in Pentylenetetrazole-Induced Seizures in Mice<br />

et al. 2019

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“…However, only GluN2A antagonism reduced epileptogenesis, seizure-induced mossy fiber sprouting, and the activity-dependent BDNF expression indicating a crucial role of this subunit in epilepsy [183]. Recently, activation of GPR40 (a Gq coupled GPCR) in the kainic-acid (KA) induced epilepsy model and PTZ-kindling model reduced susceptibility to SE, most probably reducing NMDAR surface localization by regulating the endocytosis of the receptor [184].…”

Section: Glun2a In Epilepsymentioning

confidence: 99%

Synaptic GluN2A-Containing NMDA Receptors: From Physiology to Pathological Synaptic Plasticity

Franchini

Carrano

Luca

et al. 2020

IJMS

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N-Methyl-d-Aspartate Receptors (NMDARs) are ionotropic glutamate-gated receptors. NMDARs are tetramers composed by several homologous subunits of GluN1-, GluN2-, or GluN3-type, leading to the existence in the central nervous system of a high variety of receptor subtypes with different pharmacological and signaling properties. NMDAR subunit composition is strictly regulated during development and by activity-dependent synaptic plasticity. Given the differences between GluN2 regulatory subunits of NMDAR in several functions, here we will focus on the synaptic pool of NMDARs containing the GluN2A subunit, addressing its role in both physiology and pathological synaptic plasticity as well as the contribution in these events of different types of GluN2A-interacting proteins.

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“…Their functions have been better studied in peripheral tissues, including the promotion of hormone secretion by the pancreas, lipid taste sensing and the activation of immune cells as a preliminary response toward a putative growing infection. Their participation in the CNS had less attention, although recent results suggest that some isoforms could participate in brain development, neuronal differentiation (Ma et al, 2010) and could be potential drug targets against several neuropathies, such as neuropathic pain and epilepsy (Yoshimura et al, 2015; Yang et al, 2018).…”

Section: Receptors For Fatty Acids Signalingmentioning

confidence: 99%

Fatty Acid Signaling Mechanisms in Neural Cells: Fatty Acid Receptors

Falomir-Lockhart

Cavazzutti

Giménez

et al. 2019

Front. Cell. Neurosci.

120

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Fatty acids (FAs) are typically associated with structural and metabolic roles, as they can be stored as triglycerides, degraded by β-oxidation or used in phospholipids’ synthesis, the main components of biological membranes. It has been shown that these lipids exhibit also regulatory functions in different cell types. FAs can serve as secondary messengers, as well as modulators of enzymatic activities and substrates for cytokines synthesis. More recently, it has been documented a direct activity of free FAs as ligands of membrane, cytosolic, and nuclear receptors, and cumulative evidence has emerged, demonstrating its participation in a wide range of physiological and pathological conditions. It has been long known that the central nervous system is enriched with poly-unsaturated FAs, such as arachidonic (C20:4ω-6) or docosohexaenoic (C22:6ω-3) acids. These lipids participate in the regulation of membrane fluidity, axonal growth, development, memory, and inflammatory response. Furthermore, a whole family of low molecular weight compounds derived from FAs has also gained special attention as the natural ligands for cannabinoid receptors or key cytokines involved in inflammation, largely expanding the role of FAs as precursors of signaling molecules. Nutritional deficiencies, and alterations in lipid metabolism and lipid signaling have been associated with developmental and cognitive problems, as well as with neurodegenerative diseases. The molecular mechanism behind these effects still remains elusive. But in the last two decades, different families of proteins have been characterized as receptors mediating FAs signaling. This review focuses on different receptors sensing and transducing free FAs signals in neural cells: (1) membrane receptors of the family of G Protein Coupled Receptors known as Free Fatty Acid Receptors (FFARs); (2) cytosolic transport Fatty Acid-Binding Proteins (FABPs); and (3) transcription factors Peroxisome Proliferator-Activated Receptors (PPARs). We discuss how these proteins modulate and mediate direct regulatory functions of free FAs in neural cells. Finally, we briefly discuss the advantages of evaluating them as potential targets for drug design in order to manipulate lipid signaling. A thorough characterization of lipid receptors of the nervous system could provide a framework for a better understanding of their roles in neurophysiology and, potentially, help for the development of novel drugs against aging and neurodegenerative processes.

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GPR40 modulates epileptic seizure and NMDA receptor function

Abstract: GPR40 modulates epileptic seizure and NMDA receptor function through the regulation of NR2A and NR2B surface expression.

Cited by 54 publications

References 52 publications

Effect of Captopril on Brain Oxidative Damage in Pentylenetetrazole-Induced Seizures in Mice<br />

Effect of Captopril on Brain Oxidative Damage in Pentylenetetrazole-Induced Seizures in Mice<br />

Synaptic GluN2A-Containing NMDA Receptors: From Physiology to Pathological Synaptic Plasticity

Fatty Acid Signaling Mechanisms in Neural Cells: Fatty Acid Receptors

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