PMID- 17121744
OWN - NLM
STAT- MEDLINE
DCOM- 20070220
LR  - 20220317
IS  - 1460-2156 (Electronic)
IS  - 0006-8950 (Linking)
VI  - 130
IP  - Pt 2
DP  - 2007 Feb
TI  - TGF-beta receptor-mediated albumin uptake into astrocytes is involved in 
      neocortical epileptogenesis.
PG  - 535-47
AB  - It has long been recognized that insults to the cerebral cortex, such as trauma, 
      ischaemia or infections, may result in the development of epilepsy, one of the 
      most common neurological disorders. Human and animal studies have suggested that 
      perturbations in neurovascular integrity and breakdown of the blood-brain barrier 
      (BBB) lead to neuronal hypersynchronization and epileptiform activity, but the 
      mechanisms underlying these processes are not known. In this study, we reveal a 
      novel mechanism for epileptogenesis in the injured brain. We used focal 
      neocortical, long-lasting BBB disruption or direct exposure to serum albumin in 
      rats (51 and 13 animals, respectively, and 26 controls) as well as albumin 
      exposure in brain slices in vitro. Most treated slices (72%, n = 189) displayed 
      hypersynchronous propagating epileptiform field potentials when examined 5-49 
      days after treatment, but only 14% (n = 71) of control slices showed similar 
      responses. We demonstrate that direct brain exposure to serum albumin is 
      associated with albumin uptake into astrocytes, which is mediated by transforming 
      growth factor beta receptors (TGF-betaRs). This uptake is followed by down 
      regulation of inward-rectifying potassium (Kir 4.1) channels in astrocytes, 
      resulting in reduced buffering of extracellular potassium. This, in turn, leads 
      to activity-dependent increased accumulation of extracellular potassium, 
      resulting in facilitated N-methyl-d-aspartate-receptor-mediated neuronal 
      hyperexcitability and eventually epileptiform activity. Blocking TGF-betaR in 
      vivo reduces the likelihood of epileptogenesis in albumin-exposed brains to 29.3% 
      (n = 41 slices, P < 0.05). We propose that the above-described cascade of events 
      following common brain insults leads to brain dysfunction and eventually epilepsy 
      and suggest TGF-betaRs as a possible therapeutic target.
FAU - Ivens, Sebastian
AU  - Ivens S
AD  - Institute of Neurophysiology, Charite University Medicine, Berlin, Germany.
FAU - Kaufer, Daniela
AU  - Kaufer D
FAU - Flores, Luisa P
AU  - Flores LP
FAU - Bechmann, Ingo
AU  - Bechmann I
FAU - Zumsteg, Dominik
AU  - Zumsteg D
FAU - Tomkins, Oren
AU  - Tomkins O
FAU - Seiffert, Ernst
AU  - Seiffert E
FAU - Heinemann, Uwe
AU  - Heinemann U
FAU - Friedman, Alon
AU  - Friedman A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20061121
PL  - England
TA  - Brain
JT  - Brain : a journal of neurology
JID - 0372537
RN  - 0 (Kcnj10 (channel))
RN  - 0 (Potassium Channels, Inwardly Rectifying)
RN  - 0 (Receptors, Transforming Growth Factor beta)
RN  - 0 (Serum Albumin)
RN  - RWP5GA015D (Potassium)
SB  - IM
CIN - Epilepsy Curr. 2007 Jul-Aug;7(4):105-7. PMID: 17694169
MH  - Animals
MH  - Astrocytes/*metabolism
MH  - Blood-Brain Barrier/physiopathology
MH  - Disease Models, Animal
MH  - Down-Regulation
MH  - Electroencephalography
MH  - Epilepsy/chemically induced/metabolism/*physiopathology
MH  - Magnetic Resonance Imaging
MH  - Neocortex/drug effects/metabolism/*physiopathology
MH  - Neurons/physiology
MH  - Potassium/metabolism
MH  - Potassium Channels, Inwardly Rectifying/metabolism
MH  - Rats
MH  - Rats, Wistar
MH  - Receptors, Transforming Growth Factor beta/*physiology
MH  - Serum Albumin/*pharmacokinetics/toxicity
MH  - Tissue Culture Techniques
EDAT- 2006/11/24 09:00
MHDA- 2007/02/21 09:00
CRDT- 2006/11/24 09:00
PHST- 2006/11/24 09:00 [pubmed]
PHST- 2007/02/21 09:00 [medline]
PHST- 2006/11/24 09:00 [entrez]
AID - awl317 [pii]
AID - 10.1093/brain/awl317 [doi]
PST - ppublish
SO  - Brain. 2007 Feb;130(Pt 2):535-47. doi: 10.1093/brain/awl317. Epub 2006 Nov 21.