Role(s) of the 5‐<scp>HT</scp>2C Receptor in the Development of Maximal Dentate Activation in the Hippocampus of Anesthetized Rats

Orbán, Gergely; Bombardi, Cristiano; Gammazza, Antonella Marino; Colangeli, Roberto; Pierucci, Massimo; Pomara, Cristoforo; Pessia, Mauro; Bucchieri, Fabio; Benigno, Arcangelo; Smolders, Ilse Julia; Deurwaerdère, Philippe De; Giovanni, Giuseppe Di

doi:10.1111/cns.12285

Cited by 41 publications

(46 citation statements)

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“…Thus, the fact that epilepsy and depression may share common pathogenic mechanisms and dysfunction of the serotonergic system is an obvious explanation for this bidirectional comorbidity, since defects in the serotonergic system are linked to both conditions ( Epps et al, 2012 ; Epps and Weinshenker, 2013 ). In agreement, we have showed further evidence of the involvement of both serotonergic and dopaminergic systems in the pathogenesis of epilepsy ( Cavaccini et al, 2012 ; Orban et al, 2013 ; Yague et al, 2013 ; Connelly et al, 2014 ; Crunelli and Di Giovanni, 2014 ; Orban et al, 2014 ), in depression and its pharmacological treatments ( Di Giovanni, 2008 ; Esposito et al, 2008 ). Compelling evidence for the involvement of 5-HT 1A - and 5-HT 7 -Rs in epilepsy and depression has been described, therefore it is possible to infer that agonists at these receptors might have both antiepileptic and antidepressant activity with also cognitive enhancer efficacy ( Orban et al, 2013 ).…”

Section: Do the 5-ht2a-rs Play A Role In The Comorbidity Between Epilsupporting

confidence: 88%

“…The role of pharmacological activation of 5-HT 2A -Rs in epilepsy modulation is far from being well-established, however, it might be an important potential target in light of the recent evidence that their activation might be not only be anticonvulsant but also capable of reducing seizure-related mortality due to SUDEP ( Buchanan et al, 2014 ), the leading cause of death in patients with refractory epilepsy ( Shorvon and Tomson, 2011 ). In addition, we have recently shown that mCPP and lorcaserin, two preferential 5-HT 2C -R agonists with different pharmacological profiles ( Fletcher and Higgins, 2011 ; Higgins et al, 2013 ), stop the elongation of MDA and AD induced by repetitive perforant path stimulation recorded at the level of the granular cells of the hippocampal DG acting in urethane-anesthetized rats, an effect that was not blocked by SB242084, a selective 5-HT 2C -R antagonist ( Orban et al, 2014 ). The elongation of the MDA has been considered an electroencephalographic representation of epileptogenic phenomena occurring after the first electric insult ( Stringer et al, 1989 ; Orban et al, 2013 ).…”

Section: The 5-ht 2a -Rs In the Regulation Of Epilmentioning

confidence: 99%

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Central serotonin-2A (5-HT2A) receptor dysfunction in depression and epilepsy: the missing link?

2015

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5-Hydroxytryptamine 2A receptors (5-HT2A-Rs) are G-protein coupled receptors. In agreement with their location in the brain, they have been implicated not only in various central physiological functions including memory, sleep, nociception, eating and reward behaviors, but also in many neuropsychiatric disorders. Interestingly, a bidirectional link between depression and epilepsy is suspected since patients with depression and especially suicide attempters have an increased seizure risk, while a significant percentage of epileptic patients suffer from depression. Such epidemiological data led us to hypothesize that both pathologies may share common anatomical and neurobiological alteration of the 5-HT2A signaling. After a brief presentation of the pharmacological properties of the 5-HT2A-Rs, this review illustrates how these receptors may directly or indirectly control neuronal excitability in most networks involved in depression and epilepsy through interactions with the monoaminergic, GABAergic and glutamatergic neurotransmissions. It also synthetizes the preclinical and clinical evidence demonstrating the role of these receptors in antidepressant and antiepileptic responses.

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Section: Do the 5-ht2a-rs Play A Role In The Comorbidity Between Epilsupporting

confidence: 88%

Section: The 5-ht 2a -Rs In the Regulation Of Epilmentioning

confidence: 99%

Central serotonin-2A (5-HT2A) receptor dysfunction in depression and epilepsy: the missing link?

2015

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“…Indeed, 5-HT 2C R agonists with different pharmacological profiles such as meta-chlorophenylpiperazine (mCPP) and lorcaserin, but not RO60-0175, were able to stop the elongation of the electrically triggered hippocampal maximal dentate gyrus activation in a limbic seizure model in anesthetized rats, an effect that was not blocked but rather potentiated by pre-treatment of SB 242084 (Orban et al, 2014), a selective 5-HT 2C R antagonist. In addition, 5-HT 3 Rs display also no importance in focal hippocampal seizures (Watanabe et al, 1998).…”

Section: Monoamines In Epilepsy: Preclinical and Clinical Evidencementioning

confidence: 99%

Monoaminergic Mechanisms in Epilepsy May Offer Innovative Therapeutic Opportunity for Monoaminergic Multi-Target Drugs

et al. 2016

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A large body of experimental and clinical evidence has strongly suggested that monoamines play an important role in regulating epileptogenesis, seizure susceptibility, convulsions, and comorbid psychiatric disorders commonly seen in people with epilepsy (PWE). However, neither the relative significance of individual monoamines nor their interaction has yet been fully clarified due to the complexity of these neurotransmitter systems. In addition, epilepsy is diverse, with many different seizure types and epilepsy syndromes, and the role played by monoamines may vary from one condition to another. In this review, we will focus on the role of serotonin, dopamine, noradrenaline, histamine, and melatonin in epilepsy. Recent experimental, clinical, and genetic evidence will be reviewed in consideration of the mutual relationship of monoamines with the other putative neurotransmitters. The complexity of epileptic pathogenesis may explain why the currently available drugs, developed according to the classic drug discovery paradigm of “one-molecule-one-target,” have turned out to be effective only in a percentage of PWE. Although, no antiepileptic drugs currently target specifically monoaminergic systems, multi-target directed ligands acting on different monoaminergic proteins, present on both neurons and glia cells, may represent a new approach in the management of seizures, and their generation as well as comorbid neuropsychiatric disorders.

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“…MDA was electrophysiologically characterized by (1) the onset of large-amplitude ( i.e ., 20–40 mV) population spikes (PSs) fired in bursts, and (2) a rapid increase in amplitude of DG PS 28 29 . Stimulus trains of 10 s (pulses of 0.3 ms duration, at 20 Hz) were delivered through the PP electrode at an initial intensity of 200 μA.…”

Section: Resultsmentioning

confidence: 99%

“…In view of the information available about the various roles of Hsp60 in the central nervous system, in the present study we firstly investigated the expression and distribution of Hsp60 in the rat hippocampus. We used a model of partial complex (limbic) seizures, based on the phenomenon of maximal dentate activation (MDA) recorded in the dentate gyrus (DG), which is induced by repetitive electrical stimulation of the perforant path (PP) in anesthetized rats 27 28 29 . The analysis was conducted using Western blotting and immunohistochemistry on hippocampal tissue samples.…”

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confidence: 99%

Hsp60 response in experimental and human temporal lobe epilepsy

Gammazza

Colangeli

Orbán

et al. 2015

Sci Rep

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The mitochondrial chaperonin Hsp60 is a ubiquitous molecule with multiple roles, constitutively expressed and inducible by oxidative stress. In the brain, Hsp60 is widely distributed and has been implicated in neurological disorders, including epilepsy. A role for mitochondria and oxidative stress has been proposed in epileptogenesis of temporal lobe epilepsy (TLE). Here, we investigated the involvement of Hsp60 in TLE using animal and human samples. Hsp60 immunoreactivity in the hippocampus, measured by Western blotting and immunohistochemistry, was increased in a rat model of TLE. Hsp60 was also increased in the hippocampal dentate gyrus neurons somata and neuropil and hippocampus proper (CA3, CA1) of the epileptic rats. We also determined the circulating levels of Hsp60 in epileptic animals and TLE patients using ELISA. The epileptic rats showed circulating levels of Hsp60 higher than controls. Likewise, plasma post-seizure Hsp60 levels in patients were higher than before the seizure and those of controls. These results demonstrate that Hsp60 is increased in both animals and patients with TLE in affected tissues, and in plasma in response to epileptic seizures, and point to it as biomarker of hippocampal stress potentially useful for diagnosis and patient management.

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Role(s) of the 5‐HT2C Receptor in the Development of Maximal Dentate Activation in the Hippocampus of Anesthetized Rats

Abstract: In our animal model of TLE, mCPP and lorcaserin were anticonvulsant; likely acting on receptor subtypes other than 5-HT2C. Epileptogenesis induced early adaptive changes and reorganization in the 5-HT2CR and GABA systems.

Cited by 41 publications

References 54 publications

Central serotonin-2A (5-HT2A) receptor dysfunction in depression and epilepsy: the missing link?

Central serotonin-2A (5-HT2A) receptor dysfunction in depression and epilepsy: the missing link?

Monoaminergic Mechanisms in Epilepsy May Offer Innovative Therapeutic Opportunity for Monoaminergic Multi-Target Drugs

Hsp60 response in experimental and human temporal lobe epilepsy

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