The pathophysiological mechanisms of ischemia are extremely complicated. It is difficult to confirm and maintain the therapeutic effects if only one neuroprotective agent is used. It is hypothesized that a cocktail therapy involving a combined application of neuroprotective agents is feasible and offers excellent therapeutic potential.OBJECTIVE:
To evaluate the neuroprotective effects of a cocktail therapy of insulin-like growth factor 1 (IGF1) combined with anti-intercellular adhesion molecule 1 (ICAM1) antibody in the treatment of cerebral ischemia/reperfusion injury using medical imaging, pathology, and functional neurological deficit scoring techniques.DESIGN, TIME AND SETTING:
This randomized, controlled, neuroimaging analysis of function and pathological observation was performed at the Laboratory of Molecular Imaging, Second Hospital, Hebei Medical University between September 2006 and December 2007.MATERIALS:
Transient middle cerebral artery occlusion (MCAO) was induced in 24 healthy adult cats. Anti-ICAM1 antibody and IGF1 were sourced from the Shanghai Kangcheng Biological Product Co., Ltd., China. Stereotaxic apparatus was purchased from the Center for Medical Apparatus and Instruments, Shandong Liaocheng People's Hospital, China. The in situ apoptosis kit was provided by the Beijing Zhongshan Biotechnique Co., Ltd., China.METHODS:
Twenty-four cat models of MCAO were randomly divided into four groups (n = 6): control, IGF1, anti-ICAM1 antibody and cocktail therapy. Following a 2-hour ischemia and subsequent lateral cerebral ventricular puncture, 100 μ g IGF1(cerebral ventricular), 100 μ g anti-ICAM1 antibody (i.v.), 50 μ g IGF1(lateral cerebral ventricular) + 50 μ g anti-ICAM1 antibody (i.v.), and 100 μ g physiological saline (i.v.) were administered to the IGF1, anti-ICAM1 antibody, cocktail therapy and control groups, respectively. On the following day, the same administration was performed again.MAIN OUTCOME MEASURES:
Pathological observation of the cerebral dura mater tissue surrounding the MCAO target site was performed by electron microscopy. At days 3 and 7 following MCAO induction, the volume of the cerebral infarction was measured by Philips functional neurological deficit scoring and nuclear magnetic resonance imaging.RESULTS:
Pathological observation revealed that the control group exhibited a great number of swollen neurons, glial cells and vascular endothelial cells, and showed severely injured mitochondria with an absence of the double membrane structure. The same phenomena were partially alleviated in the IGF1 and anti-ICAM1 antibody groups, and the most obvious alleviation of injuries was in the cocktail therapy group. At day 6 following MCAO establishment, the cocktail therapy group exhibited the smallest cerebral infarction volumes among the four groups (F = 71.322, P < 0.01). At days 3 and 7 following MCAO induction, the F value of Philips functional neurological deficit scoring was 10.398 and 14.430, respectively (P < 0.01); however, the best neurological functional recovery was in the cocktail therapy group.CONCLUSION:
A cocktail therapy of IGF1 combined with anti-ICAM1 antibody produces better neuroprotective effects than IGF1 or anti-ICAM1 alone, as judged by injury to mitochondria and swelling in and around neurons and glial cells.