Dilantin therapy in an experimental model of traumatic brain injury: effects of limited versus daily treatment on neurological and behavioral recovery.
The mechanisms by which Dilantin confers anticonvulsant benefits may also be neuroprotective by attenuating the acute excitatory insult in cortical and subcortical structures when the drug is given in the acute phase after traumatic brain injury (TBI). However, when Dilantin is used for prolonged periods, we hypothesized that it may impede recovery, synaptic plasticity may be impaired, and neuroprotective benefits may be lost. As such, we assessed the effect of daily chronic administration (75 mg/kg day 0 followed by 50 mg/kg daily i.p.) and acute administration (75 mg/kg day 0 followed by 50 mg/kg i.p. day 1) of Dilantin in young adult male rats on motor performance, y-maze exploration, Morris Water Maze (MWM), hippocampal (HC) cell survival, contusion size, and regional expression of neuroplasticity markers after controlled cortical impact (CCI) injury. Chronic daily Dilantin administration resulted in beam walking impairments on day 6, whereas acute Dilantin administration resulted in beam walking impairments on days 3 and 4. Chronic Dilantin administration also resulted in worse MWM performance, more HC cell loss and no increases in neuroplasticity markers compared to rats with CCI receiving chronic vehicle. Conversely, rats receiving acute Dilantin administration exhibited more novel arm exploration in the y-maze, greater HC cell sparing, and greater growth-associated protein 43 (GAP-43) expression in the HC ipsilateral to the CCI, compared to injured rats receiving vehicle. MWM was not influenced by acute Dilantin administration. These results suggest that there are beneficial effects of limited acute Dilantin therapy after TBI, and that extended daily Dilantin therapy has deleterious effects on neural recovery. These findings support clinical guidelines for limited use of Dilantin in seizure prophylaxis after TBI.
Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
Shaun D
SD
Darrah
Shaun H
SH
Darrah
Jerry
J
Chuang
Laura M
LM
Mohler
Xiangbai
X
Chen
Erin E
EE
Cummings
Tiffany
T
Burnett
M Christina
MC
Reyes-Littaua
Gary N
GN
Galang
Amy K
AK
Wagner
D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001930:Brain Injuries / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D019922:GAP-43 Protein / Q000096:biosynthesis; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D009473:Neuronal Plasticity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D010672:Phenytoin / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016708:Synaptophysin / Q000096:biosynthesis
D019922:GAP-43 Protein; D018696:Neuroprotective Agents; D016708:Synaptophysin; D010672:Phenytoin