Protective Effect of Naringin, a Citrus Flavonoid, Against Colchicine-Induced Cognitive Dysfunction and Oxidative Damage in Rats Anil Kumar, Samrita Dogra, and Atish Prakash Pharmacology Division, University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Study, Panjab University, Chandigarh, India ABSTRACT Alzheimer’s disease is a neurodegenerative disorder. Central administration of colchicine is well known to cause cognitive impairment and oxidative damage, which simulates sporadic dementia of the Alzheimer type in humans. The present study has been designed to investigate the protective effects of naringin against the colchicine-induced cognitive impairment and oxidative damage in rats. Colchicine (15 mg=5 mL), administered intracerebroventricularly, resulted in poor memory retention in both the Morris water maze and elevated plus maze task paradigms and caused marked oxidative damage. It also caused a significant decrease in acetylcholinesterase activity. Naringin (40 and 80 mg=kg, p.o.) treatment was given daily for a period of 25 days beginning 4 days prior to colchicine administration. Chronic treatment with naringin caused significant improvement in the cognitive performance and attenuated oxidative damage, as evidenced by lowering of mal- ondialdehyde level and nitrite concentration and restoration of superoxide dismutase, catalase, glutathione S-transferase, and reduced glutathione levels, and acetylcholinesterase activity compared to control. The present study highlights the therapeutic potential of naringin against colchicine-induced cognitive impairment and associated oxidative damage. KEY WORDS:  Alzheimer’s disease  colchicine  naringin  neuroprotective  oxidative stress INTRODUCTION A lzheimer’s disease (AD) is a neurodegerative disor- der that leads to cognitive impairment and loss of cholinergic neurons and their synapses, predominantly in the cerebral cortex and hippocampus area. The pathological hallmark of AD includes widespread neuritic plaques that are composed of b-amyloid and tau-rich neurofibrillary tangles. 1 The complex pathophysiology of AD involves several cellular pathways such as generation of reactive oxygen species, oxidative stress, and apoptotic injury lead- ing to nuclear degradation, among others. 2 Oxidative stress plays a key role in the onset and progression of AD. Even transient hypoxia in sporadic AD has been associated with mitochondrial dysfunction, impaired membrane integrity, and amyloid precursor protein cleavage. 3 Protein oxidation, 4 lipid peroxidation, 5 and DNA oxidation 6 have also been reported to be involved in AD progression. Centrally administered colchicine induces cognitive dysfunction and causes destruction of hippocampal granule cells, mossy fibers, and septohippocampal pathways result- ing cytoskeletal alterations and impaired axonal transport followed by progressive neuronal loss. 7,8 It induces neuro- fibrillary degeneration by binding to tubulin, the princi- pal structural protein of microtubules. 9 This leads to impairment in the intracellular trafficking of mitochondria and peroxisomes, which in turn causes synaptic loss and increased axonal excitotoxicity. 10 Colchicine also causes loss of cholinergic neurons and decreases acetylcholine transferase activity, resulting in cognitive impairment. 11 Previously, we reported that central administration of col- chicine also causes excessive free radical generation and consequently oxidative stress. 12–15 Oxidative stress is one of the primary factors involved in the pathogenesis of AD. Therefore, agents that attenuate oxidative stress by scav- enging of reactive oxygen species could be useful in the management of AD. Antioxidants like curcumin, Gingko biloba, rosmarinic acid, and huperzine A have been reported to have a neuroprotective activity in various experimental models of AD. 15–17 Naringin, a flavanone, is richly found in grapefruit (Citrus paradise, Citrus sinensis, Citrus unshiu, and Artemisia selengensis), 18 roots of Cudrania cochinchi- nensis, and fruits of Pon cirus. Research has shown that naringin possesses strong antioxidant, anti-apoptotic, anti-atherogenic, and metal chelating activities. 19–21 Recently, the protective ef- fect of naringin has been reported in an experimental model of ischemic reperfusion cerebral injury. 22 Orally administered naringin is metabolized to naringenin (4 0 ,5, 7-trihydroxyflavanone), 23 which has been shown to have good permeability across the blood–brain barrier. 24 Despite Manuscript received 25 August 2009. Revision accepted 13 April 2010. Address correspondence to: Anil Kumar, Ph.D., M.B.A., Associate Professor, Pharma- cology Division, University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Study, Panjab University, Chandigarh-160014, India, E-mail: kumaruips@ yahoo.com JOURNAL OF MEDICINAL FOOD J Med Food 13 (4) 2010, 976–984 # Mary Ann Liebert, Inc. and Korean Society of Food Science and Nutrition DOI: 10.1089=jmf.2009.1251 976