Damage to the adult CNS often causes permanent deficits. Based on a lesion model of septohippocampal pathway aspiration in the rat, we attempted to promote neuronal cell survival and post-traumatic recovery by using a pharmacological treatment combining aminoguanidine and putrescine (AGP). The functional recovery was followed over 15 weeks before morphological analysis. AGP treatment produced a persistent attenuation (approximately 50%) of the lesion-induced hyperactivity, a reduction (approximately 60%) in the sensorimotor impairments and an improved performance in the water-maze task which did not, however, rely upon improved memory capabilities. AGP weakened the lesion-induced decrease in ChAT-positive neurons in the medial septum and the extent of thalamic retrograde necrosis (by approximately 30% in each case) and resulted in a partial cholinergic reinnervation of the dentate gyrus. These promising results support the idea that coadministration of putrescine and aminoguanidine might become a potent way to foster structural and functional recovery (or compensation) in the adult mammalian CNS after injury.