The Signaling Pathways Involved in the Anticonvulsive Effects of the Adenosine A1 Receptor

Spanoghe, Jeroen; Larsen, Lars Emil; Craey, Erine; Manzella, Simona; Dycke, Annelies Van; Boon, Paul; Raedt, Robrecht

doi:10.3390/ijms22010320

Cited by 18 publications

(14 citation statements)

References 195 publications

(243 reference statements)

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“…The transcription factor NF kB regulates the expression of anti apoptotic proteins [14]. TRADD mediated degradation of the NF kB IkB complex allows the NF kB p65 isoform to translocate into the nucleus, where it regulates the transcription of a wide range of genes responsible for the synthesis of proteins, such as Bcl 2, IL 6, IL 8, and VEGF, which are involved in cell sur vival [25].…”

Section: Resultsmentioning

confidence: 99%

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Markers of Neuroinflammation and Apoptosis in the Temporal Lobe of Patients with Drug-Resistant Epilepsy

Литовченко

Zabrodskaya

Sitovskaya

et al. 2021

J Evol Biochem Phys

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Current antiepileptic strategies aim to normalize the interaction of the excitatory and inhibitory systems, which is ineffective in treating patients with drug-resistant epilepsy. Neuroinflammatory processes in the epileptic focus and its perifocal area can trigger apoptosis and also contribute to the development of drug resistance. The level of pro- and anti-apoptotic proteins (p-NF-kB, TNF-α, p53, FAS, caspase-3, caspase-9) was analyzed in intraoperative biopsies of the temporal lobe gray and white matter in the brain of patients with drug-resistant epilepsy. An increased level of pro-apoptotic proteins was revealed in the cortex and perifocal area’s white matter against the background of an imbalance of protective anti-apoptotic proteins. It appears that the activation of the extrinsic pathway of apoptosis occurs in the perifocal area, while in the epileptic focus, there are proteins responsible for the activation of the anti-apoptotic survival pathways. Active neuroinflammation in the epileptic focus and perifocal area of the temporal lobe may contribute to the development of the resistance to antiepileptic drugs and the progression of neurodegeneration in such patients.

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Section: Resultsmentioning

confidence: 99%

“…Some studies have reported the association of the nuclear factor NF kB, a master regulator of the inflammatory response, with epilepsy in ani mals [14]. NF kB consists of two subunits, and its most common form is the p65/p50 heterodimer, which typically exists in the cytoplasm in a form inhibited by the IkB protein.…”

Section: Introductionmentioning

confidence: 99%

Markers of Neuroinflammation and Apoptosis in the Temporal Lobe of Patients with Drug-Resistant Epilepsy

Литовченко

Zabrodskaya

Sitovskaya

et al. 2021

J Evol Biochem Phys

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“…In human temporal lobe epilepsy, the density of the A1Rs is increased [ 29 ] or decreased in the temporal neocortical region of the brain [ 21 ]. In animal models, however, the A1R density is decreased in rat hippocampal pyramidal neurons [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

Levetiracetam ameliorates epileptogenesis by modulating the adenosinergic pathway in a kindling model of epilepsy in mice

JAMAL,

AZAM,

KHAN

et al. 2023

Turkish Journal of Medical Sciences

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Background Levetiracetam (LEV) has been found to have an antihyperalgesic effect via acting on the adenosine system. However, the effects of LEV on the modulation of the adenosine system in the brain have not been elucidated in the prevention of seizures and epilepsy. The present study aimed to explore the possible LEV mechanisms of action in the adenosine signaling systems in an animal model of epilepsy. Methodology A docking study was initially performed to determine the possible interaction of LEV with adenosine A1 receptors (A1Rs) and equilibrative nucleoside transporters-1 (ENT1). The experimental study was divided into an acute seizure test (32 mice distributed into 4 groups) and a chronic kindling model study (40 mice distributed into 5 groups), followed by gene expression analysis and immunohistochemistry. The kindling model lasted 26 days and took 13 subconvulsive doses of pentylenetetrazole (PTZ) to completely kindle the mice in the PTZ control group. Gene expression changes in the A1Rs, potassium inwardly-rectifying channel 3.2 (Kir3.2), and ENT1 in the brain tissue samples of the mice following treatment with LEV were analyzed using reverse transcription-quantitative polymerase chain reaction, and immunohistochemistry was performed for the A1R protein expression. Results Docking studies predicted a significant interaction of LEV with A1Rs and ENT1 proteins. Results from the acute testing revealed that caffeine (100 mg/kg) and 8-cyclopentyl-1,3-dipropylxanthine (25 mg/kg) significantly reversed the antiseizure effects of LEV by reversing the percent protection and shortening the onset of the first myoclonic jerk (FMJ) and generalized clonic seizures (GCSs). In the PTZ-induced kindling, LEV demonstrated an increased gene expression of A1Rs and Kir3.2 in the brain. LEV also significantly reduced the gene expression of ENT1. Furthermore, the immunohistochemical analysis showed that LEV increased the protein expression of A1Rs in the brain. Conclusion Based on these results, it can be concluded that LEV modulates epileptogenesis by acting on the adenosine pathway in the central nervous system.

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“…Presynaptically, voltage-gated Ca 2+ channels are inhibited, resulting in reduced neurotransmitter release. Postsynaptically, G protein-mediated inwardly rectifying potassium channels are activated, resulting in membrane hyperpolarization [ 4 , 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

Ex Vivo Feedback Control of Neurotransmission Using a Photocaged Adenosine A1 Receptor Agonist

Craey

Hulpia

Spanoghe

et al. 2022

IJMS

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We report the design, synthesis, and validation of the novel compound photocaged N6-cyclopentyladenosine (cCPA) to achieve precisely localized and timed release of the parent adenosine A1 receptor agonist CPA using 405 nm light. Gi protein-coupled A1 receptors (A1Rs) modulate neurotransmission via pre- and post-synaptic routes. The dynamics of the CPA-mediated effect on neurotransmission, characterized by fast activation and slow recovery, make it possible to implement a closed-loop control paradigm. The strength of neurotransmission is monitored as the amplitude of stimulus-evoked local field potentials. It is used for feedback control of light to release CPA. This system makes it possible to regulate neurotransmission to a pre-defined level in acute hippocampal brain slices incubated with 3 µM cCPA. This novel approach of closed-loop photopharmacology holds therapeutic potential for fine-tuned control of neurotransmission in diseases associated with neuronal hyperexcitability.

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The Signaling Pathways Involved in the Anticonvulsive Effects of the Adenosine A1 Receptor

Cited by 18 publications

References 195 publications

Markers of Neuroinflammation and Apoptosis in the Temporal Lobe of Patients with Drug-Resistant Epilepsy

Markers of Neuroinflammation and Apoptosis in the Temporal Lobe of Patients with Drug-Resistant Epilepsy

Levetiracetam ameliorates epileptogenesis by modulating the adenosinergic pathway in a kindling model of epilepsy in mice

Ex Vivo Feedback Control of Neurotransmission Using a Photocaged Adenosine A1 Receptor Agonist

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