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Cellular mechanisms underlying acquired epilepsy: the calcium hypothesis of the ..
Cellular mechanisms underlying acquired epilepsy: ..
Another kindling paradigm utilizes the daily repeated injections of glutamate to induce a hyperexcitable state (, ). Although glutamate activates a number of receptor subtypes, antagonism of the NMDA receptor alone inhibits the development of hyperexcitability in this paradigm (, ; ). The role of NMDA receptors in kindling epileptogenesis is further supported by the ability of NMDA to substitute for glutamate as the kindling agent ().
Paradigms similar to those utilized in the electrical kindling model have been developed in hippocampal slice preparations wherein repeated trains of electrical stimulation result in the development of spontaneous bursting activity (). This stimulus train-induced bursting (STIB) model of epileptogenesis has differentiated the role of NMDA receptors in epileptogenesis and seizure expression. NMDA receptor antagonists inhibit the induction of stimulus train-induced epileptogenesis, but produced no anticonvulsant effects on slices that were previously made epileptic (; ; ).
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After a CNS insult, in the context of a relatively complicated set of variables including injury severity, anatomic location, physiological redundancy, and genetics, the complete spectrum of Ca2+ changes can occur at one time in different areas of the injured brain. Inherent to the Ca2+ hypothesis of epileptogenesis is the relatively, simple conception that dead neurons do not seize. Thus, neurons that survive a CNS injury are the potential substrate for the development of epilepsy. The purpose of this article is to review and summarize the evidence that long-term alterations in neuronal Ca2+ function in neurons that survive a brain insult underlie both the development and maintenance of the epileptic condition.
Essential to the Ca2+ hypothesis of epileptogenesis is this concept of the penumbra or an area of reversibly injured neurons that survive the initial SE, stroke, or TBI. Although the penumbra represents a region of injured brain wherein many neurons recover and survive, chronic alterations in the physiology of these cells may contribute, in conjunction with neuronal cell loss, to the debilitating sequelae of CNS insults. Little is known regarding the function of surviving brain tissue in the penumbra (). Since dead neurons cannot seize, we believe that the injured but surviving tissue of the penumbra or the injured brain tissue is the substrate for epileptogenesis, and that long-lasting alterations in the function of these injured, surviving neurons underlie mechanisms of epileptogenesis and the development of spontaneous recurrent seizures. Thus, the injury phase in the development of AE is essential, since it exposes neurons to abnormal Ca2+ exposure that are not lethal but are sufficient in the injury-surviving neurons to serve as the second messenger that initiates the long-term plasticity changes underlying the development of AE.
Reduced Accumulation of Creatine Kinase-MM in ..
In contrast to the pilocarpine-induced and KA-induced SE models of epileptogenesis, the kindling models of epileptogenesis utilize repetitive, subconvulsive stimulation of particular brain regions to initiate epileptogenesis (; ). Early in the protocol, electrical stimulation only elicits brief after discharges. However, after daily repetition of stimulations, after discharges increase in duration, eventually progressing to spontaneous seizure activity. Blockade of the NMDA receptor inhibits kindling epileptogenesis, demonstrating the necessity of NMDA receptor activation (, ; ).
Until recently, animal models of TBI have had difficulty demonstrating overt epileptic seizures in similar fashion as models of stroke. Despite this impediment, many investigations have demonstrated potential mechanisms of hyperexcitability after TBI. Hyperexcitability of the hippocampal dentate gyrus has been described in the popular lateral fluid percussion injury model of closed head injury in the rat and potentially attributed to alterations in hippocampal circuitry (; ; ; , ). Cytoarchitectual changes as demonstrated by selective hilar neuronal loss (; ; ; , ) and mossy fiber sprouting () have been shown and associated with dentate granule cell hyperexcitability, although some recent studies refute this hypothesis (). Larger, longer-lasting multiphasic field potential have been recorded from the hippocampus of animals after TBI compared to field potentials in controls (, ; ; ). Decreased seizure threshold has also been demonstrated in other models of TBI. A typically non-convulsant dose of pentylenetetrazol induced generalized tonic-clonic seizures in animals 15 weeks after weight drop contusion ().
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Characterization of a mutant Leishmania donovani lacking in adenosine kinase ..
such as the activation of mitogen-activated protein kinase ..
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The at the crack hypothesis of cortical ..
The steps involved in the binding of the neurotransmitter to the metabotropic receptor and the events that follow are shown in Figure 8-20C. The neurotransmitter binding to the metabotropic receptor results in the replacement of GDP by GTP on the a-subunit. The activated GTP-a-subunit dissociates from the P-y-subunit complex. Either one of these complexes can bind to effector molecules (e.g., enzymes), stimulate them (e.g., adenylate cyclase), and generate second messengers (e.g., cyclic adenosine monophosphate [cAMP]). The second messengers (e.g., cAMP) stimulate enzymes (e.g., protein kinase-A), which then phosphorylate appropriate ion channels.
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In contrast to the pilocarpine and KA models of epilepsy, which utilize convulsant drug exposure to trigger a single episode of SE, the kindling model of epileptogenesis utilizes repetitive, subconvulsive electrical stimulation of particular brain regions to initiate epileptogenesis (; ). Early in the protocol, electrical stimulation only elicits brief after discharges. However, after daily repetition of stimulations, after discharges increase in duration, eventually progressing to spontaneous seizure activity. As seen in the SE-induced AE models, blockade of the NMDA receptor inhibits kindling epileptogenesis, demonstrating the necessity of NMDA receptor activation (, ; ).
and prevented epilepto- genesis
Another kindling paradigm utilizes the daily repeated injections of glutamate to induce a hyperexcitable state (, ). Although glutamate activates a number of receptor subtypes as described above, antagonism of the NMDA receptor alone inhibits the development of hyperexcitability in this paradigm (, ; ). The role of NMDA receptors in kindling epileptogenesis is further supported by the ability of NMDA alone to substitute for glutamate as the kindling agent ().
The modification arises when a specific adenosine of the ..
Analogous kindling paradigms have been studied using in vitro preparations wherein repeated trains of electrical stimulation of hippocampal slices result in the development of spontaneous bursting activity (). This STIB model of epileptogenesis has further differentiated the role of NMDA receptors in epilepsy. NMDA receptor antagonists inhibit the induction of stimulus train-induced epileptogenesis, but produced no anticonvulsant effects on slices that were previously made epileptic (; ; ). Thus, in the STIB model, NMDA receptor activation is required for the development of the hyperexcitable state, but NMDA receptor activation is not mandatory for the initiation and expression of seizure activity once this state is achieved.
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