Biomaterial Database

Inhibition of long-term potentiation by valproic acid through modulation of cyclic AMP. 2010

Pishan Chang, and Kate E Chandler, and Robin S B Williams, and Matthew C Walker

UCL Institute of Neurology, University College London, London, UK.

OBJECTIVE Valproic acid (VPA) is widely used clinically in epilepsy, bipolar disorder, and migraine. In experimental models, it has also been shown to have neuroprotective and antiepileptogenic effects. Its mechanisms of action in these diverse conditions are, however, unclear, but there is some evidence indicating an effect of VPA upon protein kinase A (PKA) activity. We, therefore, asked whether VPA modulates cyclic adenosine monophosphate (cAMP)/PKA-dependent synaptic plasticity and whether this mode of action could explain its anticonvulsant effect. METHODS We first tested the effects of VPA on PKA-dependent synaptic plasticity at mossy fiber to CA3 synapses in rat hippocampus slices following very high-frequency stimulation or application of the adenylyl cyclase activator forskolin. Using biochemical assays, we then tested whether VPA had a direct effect on PKA activity or an indirect effect through modulating cAMP production. Lastly, VPA and inhibitors of adenylyl cyclase (SQ22536) and PKA (H89) were tested in in vitro models of epileptiform activity induced in hippocampal-entorhinal cortex slices using either pentylenetetrazol (2 mM) or low magnesium. RESULTS VPA (1 mm) inhibited PKA-dependent long-term potentiation of mossy fiber to CA3 pyramidal cell transmission. However, VPA did not directly modulate PKA activity but rather inhibited the accumulation of cAMP. In acute in vitro seizure models, the anticonvulsant activity of VPA is not mediated through modulation of adenylyl cyclase or PKA. CONCLUSIONS These results indicate that VPA through an action on cAMP accumulation can inhibit synaptic plasticity, but this cannot fully explain its anticonvulsant effect.

UI	MeSH Term	Description	Entries
D007546	Isoquinolines	A group of compounds with the heterocyclic ring structure of benzo(c)pyridine. The ring structure is characteristic of the group of opium alkaloids such as papaverine. (From Stedman, 25th ed)
D008297	Male		Males
D001921	Brain	The part of CENTRAL NERVOUS SYSTEM that is contained within the skull (CRANIUM). Arising from the NEURAL TUBE, the embryonic brain is comprised of three major parts including PROSENCEPHALON (the forebrain); MESENCEPHALON (the midbrain); and RHOMBENCEPHALON (the hindbrain). The developed brain consists of CEREBRUM; CEREBELLUM; and other structures in the BRAIN STEM.	Encephalon
D004195	Disease Models, Animal	Naturally-occurring or experimentally-induced animal diseases with pathological processes analogous to human diseases.	Animal Disease Model,Animal Disease Models,Disease Model, Animal
D004791	Enzyme Inhibitors	Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.	Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme
D004827	Epilepsy	A disorder characterized by recurrent episodes of paroxysmal brain dysfunction due to a sudden, disorderly, and excessive neuronal discharge. Epilepsy classification systems are generally based upon: (1) clinical features of the seizure episodes (e.g., motor seizure), (2) etiology (e.g., post-traumatic), (3) anatomic site of seizure origin (e.g., frontal lobe seizure), (4) tendency to spread to other structures in the brain, and (5) temporal patterns (e.g., nocturnal epilepsy). (From Adams et al., Principles of Neurology, 6th ed, p313)	Aura,Awakening Epilepsy,Seizure Disorder,Epilepsy, Cryptogenic,Auras,Cryptogenic Epilepsies,Cryptogenic Epilepsy,Epilepsies,Epilepsies, Cryptogenic,Epilepsy, Awakening,Seizure Disorders
D000242	Cyclic AMP	An adenine nucleotide containing one phosphate group which is esterified to both the 3'- and 5'-positions of the sugar moiety. It is a second messenger and a key intracellular regulator, functioning as a mediator of activity for a number of hormones, including epinephrine, glucagon, and ACTH.	Adenosine Cyclic 3',5'-Monophosphate,Adenosine Cyclic 3,5 Monophosphate,Adenosine Cyclic Monophosphate,Adenosine Cyclic-3',5'-Monophosphate,Cyclic AMP, (R)-Isomer,Cyclic AMP, Disodium Salt,Cyclic AMP, Monoammonium Salt,Cyclic AMP, Monopotassium Salt,Cyclic AMP, Monosodium Salt,Cyclic AMP, Sodium Salt,3',5'-Monophosphate, Adenosine Cyclic,AMP, Cyclic,Adenosine Cyclic 3',5' Monophosphate,Cyclic 3',5'-Monophosphate, Adenosine,Cyclic Monophosphate, Adenosine,Cyclic-3',5'-Monophosphate, Adenosine,Monophosphate, Adenosine Cyclic
D000704	Analysis of Variance	A statistical technique that isolates and assesses the contributions of categorical independent variables to variation in the mean of a continuous dependent variable.	ANOVA,Analysis, Variance,Variance Analysis,Analyses, Variance,Variance Analyses
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D000927	Anticonvulsants	Drugs used to prevent SEIZURES or reduce their severity.	Anticonvulsant,Anticonvulsant Drug,Anticonvulsive Agent,Anticonvulsive Drug,Antiepileptic,Antiepileptic Agent,Antiepileptic Agents,Antiepileptic Drug,Anticonvulsant Drugs,Anticonvulsive Agents,Anticonvulsive Drugs,Antiepileptic Drugs,Antiepileptics,Agent, Anticonvulsive,Agent, Antiepileptic,Agents, Anticonvulsive,Agents, Antiepileptic,Drug, Anticonvulsant,Drug, Anticonvulsive,Drug, Antiepileptic,Drugs, Anticonvulsant,Drugs, Anticonvulsive,Drugs, Antiepileptic