Size-controllable striatal lesion model for evaluation of neuroprotective agents in rats

Jia-Ying Chuang^{a, b}, †, Hock-Kean Liew^c, †, Cheng-Yoong Pang^{c, d}, Jon-Son Kuo^{a, c, d}

^a Institute of Pharmacology and Toxicology, Tzu Chi University, Hualien, Taiwan
^b Division of Drugs and New Biotechnology Products, Food and Drug Administration, Department of Health, Executive Yuan, Taipei, Taiwan
^c Department of Medical Research, Buddhist Tzu Chi General Hospital, Hualien, Taiwan
^d Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan

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Abstract
Objectives

Various focal brain lesions are primarily caused by excessive glutamate release. An easy and convenient in vivo striatal lesion model was developed in which reliable and controllable lesion sizes were created by glutamate for evaluation of neuroprotective agents.

Materials and Methods

Dose-dependent striatal lesions were created by intrastriatal infusion of sodium glutamate in anesthetized male Sprague-Dawley rats (250–350 g). The lesion sizes were estimated with a 2% triphenyltetrazolium chloride stain. Motor disturbances were evaluated by the rotarod test and rotational behavior test. This experimental model was attested with neuroprotective effects of granulocyte colony-stimulating factor (G-CSF, 200 μg/kg), a cytokine growth factor, and estradiol (2 mg/kg), a female sex hormone.

Results

Intrastriatal infusion of 2–6 μmol of 1 M (i.e., 2 Osm) sodium glutamate produced dose-dependent (or controllable) increases in sizes and volumes of striatal lesion in which unpredictable data were also included in analyses. The infusion rate appeared not to affect the lesion size or volume. Although the 2 Osm (1 M) glutamate solution had a much higher osmolarity than brain extracellular fluid (0.3 Osm), control infusions with the 2 Osm of glucose or sodium chloride (NaCl) produced only negligible lesions. The striatal lesion or volume induced by glutamate (4 μmol, 1 M) was reduced by pretreatment with the neuroprotective agents G-CSF and estradiol. The motor disturbance caused by glutamate infusion was also improved by G-CSF administration.

Conclusion

Local intrastriatal infusions with controlled doses of glutamate can create a reliable, controllable striatal lesion size. This model is easy and convenient for evaluation of neuroprotective agents.

Keywords
Brain damage; Estradiol; Excitotoxicity; Glutamate; Granulocyte-colony stimulating factor; Neuroprotection