Pharmacological characterization of antiepileptic drugs and experimental analgesics on low magnesium-induced hyperexcitability in rat hippocampal slices

Arias, Robert; Bowlby, Mark R.

doi:10.1016/j.brainres.2005.04.052

Cited by 19 publications

(14 citation statements)

References 48 publications

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“…Acutely applied VPA has been reported to block the paroxysmal depolarizing shift (PDS) in hippocampal CA3 neurons (Griffith and Taylor, 1988), to reduce both duration and frequency of spontaneous synchronized bursting in hippocampal CA1 and CA3 areas (Arias and Bowlby, 2005) and to inhibit the NMDAdependent PDS in amygdalar slices (Gean et al, 1994). Additionally, VPA has acute effects clinically, such as stopping status epilepticus (Sirven and Waterhouse, 2003).…”

Section: Discussionmentioning

confidence: 99%

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

Brill

Lee

Zhao

et al. 2006

Journal of Neuroscience

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Section: Discussionmentioning

confidence: 99%

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

Brill

Lee

Zhao

et al. 2006

Journal of Neuroscience

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“…Spontaneous APs generated by perfusion of zero Mg 2ϩ are thought to be a useful model of seizure activity in epileptic patients (Rafiq et al, 1995;Derchansky et al, 2004). Furthermore, clinically used AEDs such as valproate, gabapentin, and carbamazepine have demonstrated efficacy in this in vitro hyperexcitability model (Arias and Bowby, 2005). Both propofol and HS357 exhibited more pronounced block of epileptiform events than current-evoked APs.…”

Section: Discussionmentioning

confidence: 99%

“…In an effort to optimize in vitro conditions for burst firing and epileptiform events, we employed a hyperexcitation model obtained by perfusing brain slices with a zero Mg 2ϩ /7 mM K ϩ artificial cerebrospinal fluid (ACSF) solution that allows a higher magnitude depolarization and a stronger excitatory response (Mangan and Kapur, 2004;Arias and Bowby, 2005). In agreement with our in vitro studies, systemic administration of either propofol or HS357 protected mice from acute seizures observed in the 6-Hz (22-mA) partial seizure model; however, in contrast to propofol, the protection afforded by HS357 was not accompanied by motor impairment in the rotorod toxicity assay.…”

mentioning

confidence: 99%

Hydroxyamide Analogs of Propofol Exhibit State-Dependent Block of Sodium Channels in Hippocampal Neurons: Implications for Anticonvulsant Activity

Jones¹,

Wang²,

Smith³

et al. 2006

J Pharmacol Exp Ther

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Although propofol is most commonly known for its general anesthetic properties, at subanesthetic doses, propofol has been effectively used to suppress seizures during refractory status epilepticus, a mechanism, in part, attributed to the inhibition of neuronal sodium channels. In this study, we have designed and synthesized two novel analogs of propofol, HS245[2-(3-ethyl-4-hydroxy-5-isopropyl-phenyl)-3,3,3-trifluoro-2-hydroxy-propionamide] and HS357 [2-hydroxy-8-(4-hydroxy-3,5-diisopropyl-phenyl)-2-trifluoromethyl-octanoic acid amide], and determined their effects on sodium currents recorded from cultured hippocampal neurons. HS357 had greater affinity for the inactivated state of the sodium channel than propofol and HS245 (0.22 versus 0.74 and 1.2 M, respectively) and exhibited the greatest ratio of affinity for the resting over the inactivated state. HS357 also demonstrated greater use-dependent block and delayed recovery from inactivation in comparison with propofol and HS245. Under currentclamp conditions, action potentials from hippocampal CA1 neurons in slices were evoked by current injection, or following perfusion with a zero Mg 2ϩ /7 mM K ϩ artificial cerebrospinal fluid solution. Propofol and HS357 reduced the number of current-induced action potentials; however, HS357 caused a greater reduction in the number of spontaneous action potentials. Consistent with these electrophysiology studies, propofol and HS357 protected mice against acute seizures in the 6-Hz (22-mA) partial psychomotor model. Efficacious doses of propofol were associated with an impairment of motor coordination as assessed in the rotorod toxicity assay. In contrast, HS357 demonstrated a 2-fold greater protective index than propofol. Thus, propofol analogs represent an important structural class from which not only effective, but also safer, anticonvulsants may be developed.Epilepsy is a neurological disorder that affects approximately 1 to 2% of the population. Treatment of epilepsy focuses on the suppression of seizures via the use of antiepileptic drugs (AEDs) (Browne and Holmes, 2001). First generation AEDs, such as phenytoin, carbamazepine, phenobarbital, and sodium valproate, along with second generation AEDs, such as topiramate, gabapentin, lamotrigine, and zonisamide, offer a wide selection of possible therapeutic treatments for suppression of seizures. Although the number of AEDs has increased, the percentage of patients who fail to be treated successfully remains constant at an alarming 30% (Loscher and Schmidt, 2002). Substantial problems exist with toxicity, resistance, and idiosyncratic reactions in a number of the currently used AEDs (Brodie, 2001), all of which likely contribute to their failure rate. In view of this failure rate, there remains a need for a better understanding of the mechanisms involved in suppression of epileptic seizures with minimal side effects.Voltage-gated sodium channels play an important role in determining neuronal excitability and, therefore, constitute a proven target for the suppressi...

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“…Conversely, more detailed information from individual neurons may be obtained by patch-clamp recording with the resulting excitatory postsynaptic potentials or currents (EPSPs/EPSCs) being the endpoint. Additionally, spontaneous synaptic activity has been recorded by many investigators, but this has found limited utility in acute slice experiments due to a low level of unstimulated activity in control tissue, high variability, and 'crude' quantification (spike and burst counts) that is often needed [6,8,51,102,103]. Several studies of synaptic transmission in vitro and in vivo have found alterations (reductions) after ischemic events, and this is speculated to serve some protective function for the brain [5,64,183].…”

Section: Anoxia/oxygen-glucose Deprivation (Ogd)mentioning

confidence: 96%

Brain Slices as Models for Neurodegenerative Disease and Screening Platforms to Identify Novel Therapeutics

Cho

Wood²,

Bowlby³

2007

219

208

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Recent improvements in brain slice technology have made this biological preparation increasingly useful for examining pathophysiology of brain diseases in a tissue context. Brain slices maintain many aspects of in vivo biology, including functional local synaptic circuitry with preserved brain architecture, while allowing good experimental access and precise control of the extracellular environment, making them ideal platforms for dissection of molecular pathways underlying neuronal dysfunction. Importantly, these ex vivo systems permit direct treatment with pharmacological agents modulating these responses and thus provide surrogate therapeutic screening systems without recourse to whole animal studies. Virus or particle mediated transgenic expression can also be accomplished relatively easily to study the function of novel genes in a normal or injured brain tissue context.In this review we will discuss acute brain injury models in organotypic hippocampal and co-culture systems and the effects of pharmacological modulation on neurodegeneration. The review will also cover the evidence of developmental plasticity in these ex vivo models, demonstrating emergence of injury-stimulated neuronal progenitor cells, and neurite sprouting and axonal regeneration following pathway lesioning. Neuro-and axo-genesis are emerging as significant factors contributing to brain repair following many acute and chronic neurodegenerative disorders. Therefore brain slice models may provide a critical contextual experimental system to explore regenerative mechanisms in vitro.

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Pharmacological characterization of antiepileptic drugs and experimental analgesics on low magnesium-induced hyperexcitability in rat hippocampal slices

Cited by 19 publications

References 48 publications

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

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

Hydroxyamide Analogs of Propofol Exhibit State-Dependent Block of Sodium Channels in Hippocampal Neurons: Implications for Anticonvulsant Activity

Brain Slices as Models for Neurodegenerative Disease and Screening Platforms to Identify Novel Therapeutics

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