Efficacy of 3,5‐dibromo‐L‐phenylalanine in rat models of stroke, seizures and sensorimotor gating deficit

Abstract

Background and purpose: Abnormal glutamatergic activity is implicated in neurologic and neuropsychiatric disorders. Selective glutamate receptor antagonists were highly effective in animal models of stroke and seizures but failed in further clinical development because of serious side effects, including an almost complete set of symptoms of schizophrenia. Therefore, the novel polyvalent glutamatergic agent 3,5-dibromo-L-phenylalanine (3,5-DBr-L-Phe) was studied in rat models of stroke, seizures and sensorimotor gating deficit. Experimental approach: 3,5-DBr-L-Phe was administered intraperitoneally as three boluses after intracerebral injection of endothelin-1 (ET-1) adjacent to the middle cerebral artery to cause brain injury (a model of stroke). 3,5-DBr-L-Phe was also given as a single bolus prior to pentylenetetrazole (PTZ) injection to induce seizures or prior to the administration of the N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (MK-801) to cause disruption of prepulse inhibition (PPI) of startle (sensorimotor gating deficit). Key results: Brain damage caused by ET-1 was reduced by 52%, which is comparable with the effects of MK-801 in this model as reported by others. 3,5-DBr-L-Phe significantly reduced seizures induced by PTZ without the significant effects on arterial blood pressure and heart rate normally caused by NMDA antagonists. 3,5-DBr-L-Phe prevented the disruption of PPI measured 3 days after the administration of ET-1. 3,5-DBr-L-Phe also eliminated sensorimotor gating deficit caused by MK-801. Conclusion and implications:The pharmacological profile of 3,5-DBr-L-Phe might be beneficial not only for developing a therapy for the neurological and cognitive symptoms of stroke and seizures but also for some neuropsychiatric disorders.

Cerebroprotection by angiotensin-(1-7) in endothelin-1-induced ischaemic stroke

“…In previous experiments, we demonstrated that injection of ET-1 adjacent to the MCA produces effective constriction of this vessel and significant ischaemic damage to the cerebral cortex and striatum on the injected side of the brain (Cao et al 2009;Mecca et al 2009), consistent with other studies (Sharkey et al 1993). In the present set of experiments, we used an identical approach to elicit MCAO and CNS damage in normal Sprague-Dawley rats, and investigated the potential cerebroprotective actions of Ang-(1-7) applied via the I.C.V.…”

Endocrine and Neurobehavioral Abnormalities Induced by Propofol Administered to Neonatal Rats

“…PPI of startle tests were performed using the SR-Lab startle apparatus (San Diego Instruments, San Diego, CA) as previously described by our laboratory. 4,17 Testing occurred during the light phase of the dark–light cycle. At the beginning of every testing session, each animal was placed in the cylindrical animal enclosure and was then exposed to a 75-dB white noise background for a 5-min acclimation period.…”

The T-type calcium channel antagonist Z944 disrupts prepulse inhibition in both epileptic and non-epileptic rats

“…Most notably, blockade of NMDA receptors produces robust disruptions in PPI performance in rats (Klarner et al, 1998;Geyer et al, 2001). The glutamate agonist, 3,5-Dr-L-Phe, acts to both reduce seizures as well as PPI deficits caused by the NMDA antagonist, MK-801 (Cao et al, 2009). Interestingly, high doses of the NMDA agonist, d-cycloserine, reduce PPI in Sprague-Dawley rats (Depoortere et al, 1999).…”