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Query: UMLS:C0038220 (
status epilepticus
)
7,272
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Blockade of
KCa3.1
channels has been suggested as a novel strategy to reduce microglia activation. The concept has been confirmed by neuroprotective effects in a rat brain ischemia-reperfusion model and reduced microglia activation surrounding glioblastomas. Cumulating evidence exists that microglia activation significantly contributes to epileptogenesis as well as intrinsic severity in the chronic epileptic brain. Taken together these data raised the question whether the
KCa3.1
channel blocker triarylmethane-34 (TRAM-34) might also exert beneficial effects in chronic epilepsy models. In a rat post-
status epilepticus
model TRAM-34 treatment following the insult did not result in neuroprotective effects. Whereas
status epilepticus
-associated neurodegeneration remained unaffected in the piriform cortex, loss of pyramidal cells in the hippocampal CA1 and CA3a region and of neuropeptide Y-positive interneurons in the hilus proved to be exacerbated by pharmacological
KCa3.1
blockade. The development of spontaneous seizures and of behavioral and cognitive alterations was comparable in animals receiving TRAM-34 treatment or the respective vehicle. The kindling model of temporal lobe epilepsy with a massive stimulation paradigm with frequent seizure elicitation in fully kindled rats was used to assess a putative disease-modifying effect. However, sub-chronic TRAM-34 treatment failed to exert relevant effects on seizure generation and thresholds. In conclusion, the data obtained in two different chronic epilepsy models argue against using
KCa3.1
blockers as disease-modifying or antiepileptogenic agents. Exacerbation of neuronal cell loss in TRAM-34 pre-treated epileptic animals rather indicates that translational development of the compound needs to carefully consider the pathophysiological mechanisms associated with different brain insults.
...
PMID:Targeting of microglial KCa3.1 channels by TRAM-34 exacerbates hippocampal neurodegeneration and does not affect ictogenesis and epileptogenesis in chronic temporal lobe epilepsy models. 2501 31
Brain insults, such as trauma, stroke, anoxia, and
status epilepticus
(SE), cause multiple changes in synaptic function and intrinsic properties of surviving neurons that may lead to the development of epilepsy. Experimentally, a single SE episode, induced by the convulsant pilocarpine, initiates the development of an epileptic condition resembling human temporal lobe epilepsy (TLE). Principal hippocampal neurons from such epileptic animals display enhanced spike output in response to excitatory stimuli compared with neurons from nonepileptic animals. This enhanced firing is negatively related to the size of the slow afterhyperpolarization (sAHP), which is reduced in the epileptic neurons. The sAHP is an intrinsic neuronal negative feedback mechanism consisting normally of two partially overlapping components produced by disparate mechanisms. One component is generated by activation of Ca
2+
-gated K
+
(K
Ca
) channels, likely
KCa3.1
, consequent to spike Ca
2+
influx (the K
Ca
-sAHP component). The second component is generated by enhancement of the electrogenic Na
+
/K
+
ATPase (NKA) by spike Na
+
influx (NKA-sAHP component). Here we show that the K
Ca
-sAHP component is markedly reduced in male rat epileptic neurons, whereas the NKA-sAHP component is not altered. The K
Ca
-sAHP reduction is due to the downregulation of
KCa3.1
channels, mediated by cAMP-dependent protein kinase A (PKA). This sustained effect can be acutely reversed by applying PKA inhibitors, leading also to normalization of the spike output of epileptic neurons. We propose that the novel "acquired channelopathy" described here, namely, PKA-mediated downregulation of
KCa3.1
activity, provides an innovative target for developing new treatments for TLE, hopefully overcoming the pharmacoresistance to traditional drugs.
SIGNIFICANCE STATEMENT
Epilepsy, a common neurological disorder, often develops following a brain insult. Identifying key molecular and cellular mechanisms underlying acquired epilepsy is critical for developing effective antiepileptic therapies. In an experimental model of acquired epilepsy, we show that principal hippocampal neurons become intrinsically hyperexcitable. This alteration is due predominantly to the downregulation of a ubiquitous class of potassium ion channels,
KCa3.1
, whose main function is to dampen neuronal excitability.
KCa3.1
downregulation is mediated by the cAMP-dependent protein kinase A (PKA) signaling pathway. Most importantly, it can be acutely reversed by PKA inhibitors, leading to recovery of
KCa3.1
function and normalization of neuronal excitability. The discovery of this novel epileptogenic mechanism hopefully will facilitate the development of more efficient pharmacotherapy for acquired epilepsy.
...
PMID:Protein Kinase A-Mediated Suppression of the Slow Afterhyperpolarizing KCa3.1 Current in Temporal Lobe Epilepsy. 3167 89
