POLYDEOXYRIBONUCLEOTIDE (DEFIBROTIDE) PROTECTS AGAINST POSTISCHEMIC BEHAVIORAL, ELECTROENCEPHALOGRAPHIC AND NEURONAL DAMAGE IN THE GERBIL

The effectiveness of defibrotide, a single-stranded polydeoxyribonucle otide compound, in preventing damage caused by cerebral ischemia was s tudied. Global ischemia was induced in anesthetized gerbils by bilater al carotid artery occlusion for 10 min. Defibrotide (100 mg/kg) or sal ine was injected, i.v., immediately after reperfusion. The following p arameters were evaluated simultaneously: (1) electroencephalographic ( EEG) spectral power, recorded before, during and after the ischemic pe riod; (2) body temperature, monitored with a rectal thermistor probe a fter reperfusion for 120 min; (3) spontaneous motility, evaluated thro ugh a photocell system and quantified in terms of total distance trave lled in 30 min, 1 h after recirculation and at periods over 15 days; ( 4) mnemonic functions assessed by passive avoidance test from 3 to 15 days after ischemia; (5) histological examination, 7 days after reperf usion, counting CAI hippocampal neuronal cells, The ischemia-induced c omplete flattening of spectral power was significantly reversed (P < 0 .01) by post-ischemic treatment with defibrotide between 30 and 90 min after ischemia. A complete recovery of total EEG spectral power was s een in the defibrotide group at 6 h and the saline ischemic group at 1 day. Seven days after bilateral carotid occlusion, there was a signif icant decrease in spectral power (-70% +/- 6) together with a loss of the number of CA1 cells in the saline ischemic group (-64%). Treatment with defibrotide significantly protected against the decrease in spec tral power (-30% +/- 7) and cell loss (-9%). Finally, the number of an imals found to be protected against the ischemia-induced flattening wa s significantly larger for defibrotide-treated gerbils than for saline -treated animals throughout the experiment except for the third day. B ody temperature was significantly decreased only at 30 min after reper fusion in bath ischemic and sham-operated groups. Defibrotide reduced ischemia-induced hypermotility but only 6 h after the insult. The isch emia-induced impairment of memory was partially reversed within 3 days in the defibrotide-treated animals and fully reversed within 7 days i n the defibrotide group and 15 days in the saline group. Our results d emonstrate that defibrotide, even when administered after the post-isc hemic period, possesses anti-ischemic properties. The mechanism by whi ch defibrotide protects the ischemic reperfused brain is still largely unknown. However, a neuroprotection via adenosine A, and A, subtype r eceptor interaction can be put forward.