DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

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SECTION II
NEUROPHARMACOLOGY
Figure 21–1. Relations among cortical EEG, extracellular, and intracellular recordings in a seizure focus induced by local application
of a convulsant agent to mammalian cortex. The extracellular recording was made through a high-pass filter. Note the high-frequency
firing of the neuron evident in both extracellular and intracellular recording during the paroxysmal depolarization shift (PDS).
(Modified with permission from Ayala GF, Dichter M, Gumnit RJ, et al. Genesis of epileptic interictal spikes. New knowledge of cortical
feedback systems suggests a neurophysiological explanation of brief paroxysms. Brain Res, 1973, 52:1–17. Copyright © Elsevier.)
One model, termed “kindling,” is induced by periodic administration
of brief, low-intensity electrical stimulation of the amygdala
or other limbic structures. Initial stimulations evoke a brief
electrical seizure recorded on the EEG without behavioral change,
but repeated (e.g., 10-20) stimulations result in progressive intensification
of seizures, culminating in tonic-clonic seizures. Once established,
the enhanced sensitivity to electrical stimulation persists for
the life of the animal. Despite the exquisite propensity to intense
seizures, spontaneous seizures or a truly epileptic condition do not
occur until 100-200 stimulations have been administered. The ease
of control of kindling induction (i.e., stimulations administered at
the investigator’s convenience), its graded onset, and the ease of
quantitating epileptogenesis (number of stimulations required to
evoke tonic-clonic seizures) simplify experimental study. In mice,
deletion of the gene encoding the receptor tyrosine kinase, TrkB,
prevents epileptogenesis in the kindling model (He et al., 2004),
which advances TrkB and its downstream signaling pathways as
attractive targets for developing small molecule inhibitors for prevention
of epilepsy or its progression.
Additional models are produced by induction of continuous
seizures for hours (“status epilepticus”), with the inciting agent being
a chemoconvulsant, such as kainic acid or pilocarpine, or sustained
electrical stimulation. The fleeting episode of status epilepticus is
followed weeks later by the onset of spontaneous seizures, an
intriguing parallel to the scenario of complicated febrile seizures in
young children preceding the emergence of spontaneous seizures
years later. In contrast to the limited or absent neuronal loss characteristic
of the kindling model, overt destruction of hippocampal neurons
occurs in the status epilepticus models, reflecting aspects of
hippocampal sclerosis observed in humans with severe limbic
seizures. Indeed, the discovery that complicated febrile seizures precede
and presumably are the cause of hippocampal sclerosis in
young children (VanLandingham et al., 1998) establishes yet another
commonality between these models and the human condition.
Several questions arise with respect to these models. What
transpires during the latent period between status epilepticus and
emergence of spontaneous seizures that causes the epilepsy? Might
an anti-epileptogenic agent that was effective in one of these models
be effective in other models?
Important insights into the mechanisms of action
of drugs that are effective against partial seizures have
emerged in the past two decades (Rogawski and
Loscher, 2004). These insights largely have come from
electrophysiological studies of relatively simple in vitro
models, such as neurons isolated from the mammalian
CNS and maintained in primary culture. The experimental
control and accessibility provided by these