Brain-derived neurotrophic factor but not forced arm use improves long-term outcome after photothrombotic stroke and transiently upregulates binding densities of excitatory glutamate receptors in the rat brain.
OBJECTIVE
Both application of neurotrophic factors like brain-derived neurotrophic factor (BDNF) and constraint-induced movement therapy like forced arm use have been shown to potentially improve outcome after stroke. The aim of the present study was to check whether postischemic long-term outcome correlates to specific modifications in the abundance of various neurotransmitter receptors.


METHODS
Adult male Wistar rats were subjected to photothrombotic ischemia and assigned to various treatment groups (n=5 each) with end points at 3 and 6 weeks: (1) ischemic control (saline); (2) BDNF (ischemia, 20 microg BDNF); (3) forced arm use (ischemia, saline, and ipsilateral plaster cast for 5 or 14 days for the 3- and 6-week groups, respectively); and (4) combined treatment (combi; ischemia, 20 microg BDNF, forced arm use). Animals received intravenous bolus infusions of saline or BDNF 1 hour 3 and 5 days after ischemia, respectively. A group of sham rats (n=2) served as a control. A battery of behavioral tests was performed before and up to 6 weeks after ischemia. Quantitative in vitro receptor autoradiography was performed on 12-microm-thick cryostat sections using [(3)H]MK-801, [(3)H]AMPA, and [(3)H]muscimol for labeling of NMDA, AMPA, and GABA(A) receptors, respectively.


RESULTS
Best functional outcome was seen after BDNF treatment, whereas vice versa rats with forced arm use did worse in behavioral performance. Improved behavioral outcome was associated with increased perilesional binding densities of NMDA and AMPA receptors 3 weeks after stroke.


CONCLUSIONS
Our findings suggest that transient enhanced neurotransmission as reflected by increased ligand binding of NMDA and AMPA receptors may participate in successful postlesional reorganization processes.
Müller
Harald D
HD
Department of Neuropathology, Johannes Gutenberg-University of Mainz, Mainz, Germany.
Hanumanthiah
Kiran M
KM
Diederich
Kai
K
Schwab
Stefan
S
Schäbitz
Wolf-Rüdiger
WR
Sommer
Clemens
C
D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000627:therapeutic use*; D002544:Cerebral Infarction / Q000209:etiology / Q000473:pathology; D016291:Dizocilpine Maleate / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism; D005552:Forelimb; D018755:GABA Agonists / Q000378:metabolism; D020767:Intracranial Thrombosis / Q000150:complications; D008024:Ligands; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009118:Muscimol / Q000378:metabolism; D026741:Physical Therapy Modalities; D051381:Rats; D017208:Rats, Wistar; D017470:Receptors, Glutamate / Q000378:metabolism*; D012149:Restraint, Physical; D020521:Stroke / Q000209:etiology / Q000503:physiopathology / Q000628:therapy*; D015854:Up-Regulation; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D018691:Excitatory Amino Acid Antagonists; D018755:GABA Agonists; D008024:Ligands; D017470:Receptors, Glutamate; D009118:Muscimol; D016291:Dizocilpine Maleate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid