Chronic Valproic Acid Treatment Triggers Increased Neuropeptide Y Expression and Signaling in Rat Nucleus Reticularis Thalami

Brill, Julia; Lee, Michelle; Zhao, Sheng; Fernald, Russell D.; Huguenard, John R.

doi:10.1523/jneurosci.5320-05.2006

Cited by 36 publications

(29 citation statements)

References 57 publications

(68 reference statements)

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“…NPY was found to be expressed in virtually all neurons within the nRt (Fig. 4A), but no significant expression was found in thalamic relay nuclei [2], which is consistent with the notion that NPY is generally expressed by GABAergic interneurons. Y 1 receptors were found to be expressed at intermediate levels in nRt neurons and at higher levels in neurons of relay nuclei (Fig.…”

Section: Y 1 Receptor Expression In Nrt and Relay Nucleisupporting

confidence: 86%

“…Our results underscore that NPY can function as an endogenous anticonvulsant in spike-wave seizures of absence epilepsy [2,23,25]. Understanding the modulatory action of NPY and specifying which Y receptors mediate a given effect contributes towards a better understanding of thalamic oscillations and may possibly highlight novel routes for treatment of absence seizures.…”

Section: Discussionmentioning

confidence: 52%

“…In the hippocampus, increased NPY expression is thought to be a compensatory effect of kindling and epileptogenesis [19,22,30,31], in vivo experiments in GEARS rats demonstrate that NPY suppresses absence seizures [23] and the anticonvulsant valproic acid has been proposed to act at least in part via an upregulation of NPY expression in hippocampus and nRt [2].…”

Section: Introductionmentioning

confidence: 99%

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NPY signaling through Y1 receptors modulates thalamic oscillations

2007

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Neuropeptide Y is the ligand of a family of G-protein coupled receptors (Y 1 to Y 6 ). In the thalamus, exogenous and endogenously released NPY can shorten the duration of thalamic oscillations in brain slices from P13 to P15 rats, an in vitro model of absence seizures. Here, we examine which Y receptors are involved in this modulation. Application of the Y 1 receptor agonist Leu 31 Pro 34 NPY caused a reversible reduction in the duration of thalamic oscillations (−26.6 +/− 7.8%), while the Y 2 receptor agonist peptideYY and the Y 5 receptor agonist BWX-46 did not exert a significant effect. No Y receptor agonist affected oscillation period. Application of antagonists of Y 1 , Y 2 and Y 5 receptors (BIBP3226, BIIE0246 and L152,806, respectively) produced results consistent with those obtained from agonists. BIBP3226 caused a reversible disinhibition, an effect that increases oscillation duration (18.2 +/− 9.7%) while BIIE0246 and L152,806 had no significant effect. Expression of NPY is limited to neurons in the reticular thalamic nucleus (nRt), but Y 1 receptors are expressed in both nRt and adjacent thalamic relay nuclei. Thus, intra-nRt or nRt to relay nucleus NPY release could cause Y 1 receptor mediated inhibition of thalamic oscillations.

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Section: Y 1 Receptor Expression In Nrt and Relay Nucleisupporting

confidence: 86%

Section: Discussionmentioning

confidence: 52%

Section: Introductionmentioning

confidence: 99%

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NPY signaling through Y1 receptors modulates thalamic oscillations

2007

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“…59 Neuropeptide Y is an endogenous anticonvulsant and it has a measurable effect on synchronized neuronal activity. 60 Since VPA is used in the management of absence and complex partial seizures, specific neuropeptide Y upregulation in rat nucleus reticularis thalami involved in the propagation of absence and temporal lobe seizures may constitute one of its clinical mechanisms of action.…”

Section: Conjugation Products Of Valproic Acid and Neuroinhibitory Ammentioning

confidence: 99%

Valproic Acid: Second Generation

2007

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Summary:The manuscript focuses on structure-activity relationship studies of CNS-active compounds derived from valproic acid (VPA) that have the potential to become secondgeneration VPA drugs. Valproic acid is one of the four most widely prescribed antiepileptic drugs (AEDs) and is effective (and regularly approved) in migraine prophylaxis and in the treatment of bipolar disorders. Valproic acid is also currently undergoing clinical trials in cancer patients. Valproic acid is the least potent of the established AEDs and its use is limited by two rare but potentially life-threatening side effects, teratogenicity and hepatotoxicity. Because AEDs treat the symptoms (seizure) and not the cause of epilepsy, epileptic patients need to take AEDs for a long period of time. Consequently, there is a substantial need to develop better and safer AEDs. To become a successful second-generation VPA, the new drug should possess the following characteristics: broad-spectrum antiepileptic activity, better potency than VPA, lack of teratogenicity and hepatotoxicity, and a favorable pharmacokinetic profile compared with VPA including a low potential for drug interactions.

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“…In particular, interneurons expressing gammaaminobutyric acid (GABA), the principal inhibitory neurotransmitter in the human brain, are essential for normal neuronal synchronization and maintenance of a seizure threshold in humans (Cossette et al 2002), rodents (Delorey et al 1998), and zebrafish (Baraban et al 2005). A failure of the brain to properly regulate neuronal synchrony can result from ion channel defects (Xu and Clancy 2008), neuropeptide depletion (Brill et al 2006), brain malformations (Patel et al 2004), interneuron loss (Cobos et al 2005), and/or synaptic vesicle recycling failure (Di Paolo et al 2002), all of which may be caused by disrupting the nerve-cell cytoskeleton. Therefore, further exploration of putative links between cytoskeletal components and neurotransmission may accelerate development of novel therapeutics for epilepsy.…”

mentioning

confidence: 99%

Pharmacogenetic Analysis Reveals a Post-Developmental Role for Rac GTPases inCaenorhabditis elegansGABAergic Neurotransmission

et al. 2009

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The nerve-cell cytoskeleton is essential for the regulation of intrinsic neuronal activity. For example, neuronal migration defects are associated with microtubule regulators, such as LIS1 and dynein, as well as with actin regulators, including Rac GTPases and integrins, and have been thought to underlie epileptic seizures in patients with cortical malformations. However, it is plausible that post-developmental functions of specific cytoskeletal regulators contribute to the more transient nature of aberrant neuronal activity and could be masked by developmental anomalies. Accordingly, our previous results have illuminated functional roles, distinct from developmental contributions, for Caenorhabditis elegans orthologs of LIS1 and dynein in GABAergic synaptic vesicle transport. Here, we report that C. elegans with function-altering mutations in canonical Rac GTPase-signaling-pathway members demonstrated a robust behavioral response to a GABA A receptor antagonist, pentylenetetrazole. Rac mutants also exhibited hypersensitivity to an acetylcholinesterase inhibitor, aldicarb, uncovering deficiencies in inhibitory neurotransmission. RNA interference targeting Rac hypomorphs revealed synergistic interactions between the dynein motor complex and some, but not all, members of Rac-signaling pathways. These genetic interactions are consistent with putative Rac-dependent regulation of actin and microtubule networks and suggest that some cytoskeletal regulators cooperate to uniquely govern neuronal synchrony through dynein-mediated GABAergic vesicle transport in C. elegans.

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Chronic Valproic Acid Treatment Triggers Increased Neuropeptide Y Expression and Signaling in Rat Nucleus Reticularis Thalami

Cited by 36 publications

References 57 publications

NPY signaling through Y1 receptors modulates thalamic oscillations

NPY signaling through Y1 receptors modulates thalamic oscillations

Valproic Acid: Second Generation

Pharmacogenetic Analysis Reveals a Post-Developmental Role for Rac GTPases inCaenorhabditis elegansGABAergic Neurotransmission

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