Gender differences in susceptibility to kainic acid-induced neurodegeneration in aged C57BL/6 mice Xing-Mei Zhang a,b , Shun-Wei Zhu a , Rui-Sheng Duan a , Abdul H. Mohammed a , Bengt Winblad a , Jie Zhu a,b, * a Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Stockholm, Sweden b Department of Neurology, The First Hospital, Jilin University, Changchun, China Received 30 October 2007; accepted 29 January 2008 Available online 8 February 2008 Abstract Some epidemiological studies concerning gender differences in Alzheimer’s disease (AD) support the higher prevalence and incidence of AD in women, while most studies using animal models of aging have included only male subjects. It is still uncommon for aged males and females to be compared in the same study. In the present study, we investigated how age and gender influence the excitotoxic neurodegeneration by treating C57BL/6 mice (aged females and males as well as adult females and males) with kainic acid (KA) intranasally. Clinical signs, behavioural changes, pathological changes and astrocyte proliferation were tested; and the levels of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) were measured after KA treatment. The results showed that aged female mice were more sensitive to KA-induced excitotoxicity as demonstrated by severer seizure activity, increased locomotion and rearing in open-field test, prominent hippocampal neuronal damage, enhanced astrocyte proliferation compared with aged males, adult females and adult male mice. In addition, higher BDNF level in hippocampus of aged female mice was observed. These results denote the disparity of aging and gender in KA-induced hippocampal neurodegeneration and aged female mice are more sensitive to the excitotoxicity. # 2008 Elsevier Inc. All rights reserved. Keywords: Aging; Gender; Kainic acid; Neurodegeneration; BDNF 1. Introduction An increased vulnerability of aged individuals to the neurological or epileptogenic effects of domoic acid (DOM) in humans and of kainic acid (KA) in rats has been described (Benkovic et al., 2006; Dawson and Wallace, 1992; Perl et al., 1990). Several factors that change with age might influence brain sensitivity to excitotoxic damage, including the density of glutamate receptor, the uptake and release of neurotrans- mitters, and cellular metabolic processes (Massieu and Tapia, 1997). Significant decreases have been detected for the N- methyl-D-aspartate (NMDA) and kainate receptor-binding sites in most of the cortical areas in aging mice (Magnusson and Cotman, 1993). Some findings have demonstrated that there is a gender- associated difference in the aged brain to the neurodegeneration (Markham et al., 2005). Aged female Long-Evans (LE) rats show a greatly enhanced susceptibility to KA-induced seizures even at doses fourfold lower than that of adult controls (Dawson and Wallace, 1992). The epidemiological studies concerning gender differences in Alzheimer’s disease (AD) also support the higher prevalence and incidence of AD in women (Andersen et al., 1999; Fratiglioni et al., 1997). A recent study using positron emission tomography explored gender differences in the regional cerebral metabolic rate of glucose in patients with AD and found that, at the same level of severity of cognitive impairment, men showed a significantly greater hypometabolism than women. This suggests that men can compensate more pathology than women and men are less likely to express neurodegeneration as clinical dementia (Perneczky et al., 2007). However, the mechanisms responsible Available online at www.sciencedirect.com NeuroToxicology 29 (2008) 406–412 * Corresponding author at: Division of Neurodegeneration, Department of Neurobiology, Care Sciences and Society, Karolinska University Hospital, Huddinge, 141 86 Stockholm, Sweden. Tel.: +46 8 58585494; fax: +46 8 58585470. E-mail address: jie.zhu@ki.se (J. Zhu). 0161-813X/$ – see front matter # 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.neuro.2008.01.006