Intranasal delivery of a thyrotropin-releasing hormone analog attenuates seizures in the amygdala-kindled rat.
OBJECTIVE
Thyrotropin-releasing hormone (TRH) is known to have anticonvulsant effects in several animal seizure models and is efficacious in treating patients with certain intractable epilepsies. However, the duration of TRH's action is limited due to low bioavailability and difficulty penetrating the blood-brain barrier (BBB). Since direct nose to brain delivery of therapeutic compounds may provide a means for overcoming these barriers, we utilized the kindling model of temporal lobe epilepsy to determine if intranasal administration of a TRH analog, 3-methyl-histidine TRH (3Me-H TRH), could significantly inhibit various seizure parameters.


METHODS
Kindling was accomplished using a 1s train of 60 Hz biphasic square wave (200 microA peak to peak) administered daily to the basolateral amygdala until the animal was fully kindled. Afterdischarge duration (ADD) was assessed via electroencephalographs (EEGs) recorded bilaterally from bipolar electrodes in the basolateral amygdala and behavioral seizure severity (stage I-V) was simultaneously recorded digitally. Kindled subjects received 3Me-H TRH (10(-9), 10(-8), 10(-7) M) intranasally 60 and 30 min prior to amygdala stimulation. The ADD and seizure stage was compared to control kindled animals receiving physiological saline intranasally.


RESULTS
Intranasal application of 3Me-H TRH resulted in a concentration-dependent reduction in total seizure ADD. Additionally, the analog had significant concentration-dependent effects on behavioral stages I through IV (partial) and stage V (generalized) seizures. However, 3Me-H TRH significantly reduced clonus duration only at the highest concentration.


CONCLUSIONS
The results indicate that intranasal delivery of TRH/analogs may be a viable means to suppress temporal lobe seizures and perhaps other seizure disorders.
Veronesi
Michael C
MC
Program in Medical Neurobiology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Kubek
Daniel J
DJ
Kubek
Michael J
MJ
D000208:Acute Disease; D000281:Administration, Intranasal; D000679:Amygdala / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004569:Electroencephalography / Q000187:drug effects / Q000706:statistics & numerical data; D004833:Epilepsy, Temporal Lobe / Q000209:etiology / Q000517:prevention & control*; D007839:Functional Laterality / Q000187:drug effects / Q000502:physiology; D015918:Infusion Pumps, Implantable; D007696:Kindling, Neurologic / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012965:Sodium Chloride / Q000008:administration & dosage; D013973:Thyrotropin-Releasing Hormone / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use
D012965:Sodium Chloride; D013973:Thyrotropin-Releasing Hormone