L-NIO as a novel mechanism for inducing focal cerebral ischemia in the adult rat brain.
BACKGROUND
Ischemic stroke is the most frequent cause of persistent neurological disability in Western societies. New treatment strategies are required and effective in vivo models are crucial to their development.


METHODS
The current study establishes a novel in vivo rat model of focal striatal ischemia using the vasoconstrictive agent N5-(1-iminoethyl)-L-ornithine (L-NIO). Adult male Sprague Dawley rats received a unilateral intrastriatal infusion of L-NIO in combination with jugular vein occlusion.


RESULTS
L-NIO infusion was associated with zero mortality, low surgical complexity and a reproducible infarct, providing advantages over established models of focal ischemia. The mean infarct volume of 8.5±5.3% of the volume of the contralateral striatum resulted in blood-brain barrier dysfunction, neuronal hypoxia and ongoing neurodegeneration. Further characteristics of ischemic stroke were exhibited, including robust microglia/macrophage and astroglial responses lasting at least 35 days post-ischemia, in addition to chronic motor function impairment.


METHODS
When compared to other models such as the MCAo models, the consistency in regions affected, high success rate, zero mortality, reduced surgical complexity and minimal welfare requirements of the L-NIO model make it ideal for initial high-throughput investigations into preclinical efficacy and proof of principle studies of acute ischemic stroke interventions.


CONCLUSIONS
We propose that the L-NIO rat model of focal striatal ischemia does not replace the use of other ischemic stroke models. Rather it provides a new, complementary tool for initial preclinical investigations into the treatment of ischemic stroke.
Department of Pharmacology and Clinical Pharmacology, Centre for Brain Research, School of Medical Science, FMHS, University of Auckland, Auckland, New Zealand.
Amelia R
AR
Van Slooten
Department of Pharmacology and Clinical Pharmacology, Centre for Brain Research, School of Medical Science, FMHS, University of Auckland, Auckland, New Zealand.
Yuhui
Y
Sun
Department of Anatomy, Brain Health Research Centre, University of Otago, Dunedin, New Zealand; Department of Psychology, Brain Health Research Centre, University of Otago, Dunedin, New Zealand.
Andrew N
AN
Clarkson
Department of Pharmacology and Clinical Pharmacology, Centre for Brain Research, School of Medical Science, FMHS, University of Auckland, Auckland, New Zealand. Electronic address: b.connor@auckland.ac.nz.
Bronwen J
BJ
Connor
D000818:Animals; D001812:Blood-Brain Barrier / Q000503:physiopathology; D020520:Brain Infarction / Q000209:etiology; D002545:Brain Ischemia / Q000150:complications / Q000209:etiology*; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D007601:Jugular Veins / Q000503:physiopathology; D008297:Male; D009069:Movement Disorders / Q000209:etiology / Q000517:prevention & control; D009410:Nerve Degeneration / Q000209:etiology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D018696:Neuroprotective Agents / Q000627:therapeutic use; D009952:Ornithine / Q000031:analogs & derivatives* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; C065027:N(G)-iminoethylornithine; D016291:Dizocilpine Maleate; D009952:Ornithine
Animal model; Behavior; Focal ischemia; Inflammation; Striatum; Stroke