DAMAGE OF SUBCLICIAL EPILEPTIFORM
DISCHARGES ON BRAIN NEURONS IN RATS AND ITS NEUROBIOLOGICAL MECHANISMS
Cai FC, Wang QS
Children’s Hospital, Chongqing, China
Objective: To
demonstrate the impairment of subclinical epileptiform discharges (SED) on brain
fuction , and to explore its pathological as well as neurobiological basis
because of the high incidence of SED(3.54-10% in healthy children) and of
transient cognitive impairment (TCI, more than 50% in SED children).
Methods: Wistar rats
were successfully used for establishing the SED model by subconvulsive
electrical stimulation at frontal lobe and hippocampus respectively. Cortical
functions were tested by activity in an unfamiliar open field, resistance
to capture, and spatial learning ability in Morris water maze. The cellular
neurobiological changes were dynamically observed, including intracellular Ca2+,
calmodulin (CaM), total CaM, Ca2+/CaM dependent kinase II α
(CaMKIIα), NOS, nNOS, Na+-K+-ATPaseCa2+-
ATPase detected by Fura-2/AM, flowcytometry, Western blotting,
immunochemistry or in situ hybridization respectively. Histological study
for hippocampal region was finished electronmicroscopically.
Results: (1) Significant
abnormality of emotional behaviors in SED rats, even in 72hs after the last
stimulation, including hypersensitive frighten to sound, decreasing
activity in open-field, increased resistance to capture, and poorly
performing on Morris water maze; (2) Distinct ultrastructural alterations in
SED brains, even though in 72hs post-stimulation, including neuronal
degeneration, swelling of gliocyte synapse and myelin, as well
microcirculatory disturbance, but more predominantly at hippocampus regardless
the site of stimulation; (3) Significantly increased NO or NOS level and remarkable
expressions of nNOS and nNOS-mRNA in SED brain, especially at hippocampus
region; (4) Significantly elevated activities of Na+-K+-ATPase
and Ca2+-ATPase in brain homogenates and mitochondria. It
suggests that SED may result in dysfunction of neuronal ion pump and
mitochondria damage which could lead to the disorders of energy metabolism;
(5) Significantly increased Intracellular
free Ca2+ and CaM but remarkble decreased CaMKIIα in SED brain..
Conclusion:
SED does disturb cortex functions as emotional behavior, learning and
memory; and result in remarkable neurobiological alterations, particualr
vulnerability at hippocampus, although the alterations could be reversible
in the limited observation period. It could be presumed that more severe or
persistent effects on brain neurons after more lasting and frequent SED. It
is necessary to regard TCI as one of clinic issue and certain
neuropsychological tests should be considered for patients with frequent
SEDs. It should be valuable to explore the value of medications to prevent
CNS damages from frequent SEDs.