Neither in vivo MRI nor behavioural assessment indicate therapeutic efficacy for a novel 5HT(1A) agonist in rat models of ischaemic stroke.
BACKGROUND
5HT1A agonists have previously been shown to promote recovery in animal models of stroke using ex vivo outcome measures which have raised the hopes for a potential clinical implementation. The purpose of this study was to evaluate the potential neuroprotective properties of a novel 5HT1A agonist DU123015 in 2 different models of transient focal ischaemic stroke of varying severities using both in vivo neuroimaging and behavioural techniques as primary outcome measures. For these studies, the NMDA receptor antagonist MK-801 was also utilized as a positive control to further assess the effectiveness of the stroke models and techniques used.


RESULTS
In contrast to MK-801, no significant therapeutic effect of DU123015 on lesion volume in either the distal MCAo or intraluminal thread model of stroke was found. MK-801 significantly reduced lesion volume in both models; the mild distal MCAo condition (60 min ischaemia) and the intraluminal thread model, although it had no significant impact upon the lesion size in the severe distal MCAo condition (120 min ischaemia). These therapeutic effects on lesion size were mirrored on a behavioural test for sensory neglect and neurological deficit score in the intraluminal thread model.


CONCLUSIONS
This study highlights the need for a thorough experimental design to test novel neuroprotective compounds in experimental stroke investigations incorporating: a positive reference compound, different models of focal ischaemia, varying the duration of ischaemia, and objective in vivo assessments within a single study. This procedure will help us to minimise the translation of less efficacious compounds.
Ashioti
Maria
M
Institute of Psychiatry, Kings College London, Denmark Hill, UK. m.ashioti@iop.kcl.ac.uk
Beech
John S
JS
Lowe
Andrew S
AS
Bernanos
Michel
M
McCreary
Andrew
A
Modo
Michel M
MM
Williams
Steve C R
SC
D000818:Animals; D002540:Cerebral Cortex / Q000473:pathology*; D019610:Cytoprotection / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000627:therapeutic use; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008279:Magnetic Resonance Imaging; D008297:Male; D009474:Neurons / Q000187:drug effects; D009483:Neuropsychological Tests; D017063:Outcome Assessment, Health Care; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000627:therapeutic use*; D013997:Time Factors
D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists; D016291:Dizocilpine Maleate