Genistein improves sensorimotor gating: Mechanisms related to its neuroprotective effects on the striatum Esther T. Menze, Ahmed Esmat, Mariane G. Tadros, Amani E. Khalifa, Ashraf B. Abdel-Naim * Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt article info Article history: Received 28 May 2015 Received in revised form 21 December 2015 Accepted 4 January 2016 Available online 5 January 2016 Keywords: Huntington's disease 3-Nitropropionic acid Prepulse inhibition Genistein 17b-estradiol abstract Huntington's disease (HD) is a neurodegenerative disorder, characterized by selective atrophy in the striatum, particularly the medium spiny GABAergic efferent neurons. This results in striatal sensorimotor gating deficits. Systemic administration of 3-nitropropionic acid (3-NPA) produces selective lesions mimicking those of HD. Males were found to be more susceptible to 3-NPA-induced neurotoxicity than females, suggesting neuroprotective effects of estrogens. Phytoestrogens, including genistein, are good estrogenic alternatives that keep their beneficial effects on non-reproductive organs and lack the po- tential hazardous side effects. The current study was designed to investigate the potential beneficial effects of genistein in 3-NPA-induced HD in ovariectomized rats. Results showed that 3-NPA (20 mg/kg) administration caused significant disruption of the rats' locomotor activity and prepulse inhibition. In addition, it decreased striatal ATP levels and increased oxidative stress, inflammatory and apoptotic markers with striatal focal hemorrhage and gliosis. Pretreatment with 17b-estradiol (2.5 mg/kg) or genistein (20 mg/kg) led to a significant improvement of behavioral parameters, increased ATP pro- duction, decreased oxidative stress, attenuated inflammation and apoptosis. Therefore, this study sug- gests potential neuroprotective effects of genistein in ovariectomized rats challenged with 3-NPA. © 2016 Elsevier Ltd. All rights reserved. 1. Introduction Huntington's disease (HD) is an autosomal dominant progres- sive neurodegenerative disorder characterized by abnormalities of movement, emotion and cognition (Folstein, 1989). Such disease is characterized by selectivity of atrophy and neuronal loss. The most prominent atrophy is found in the corpus striatum (Vonsattel et al., 1985), particularly in the medium spiny GABAergic efferent neu- rons. This results in striatal gating mechanisms deficits and development of adventitious choreiform movements (Bruyn, 1968). Impaired gating of motor responses can be quantified from the startle reflex which is defined as the contraction of the facial and skeletal muscles to sudden relatively intense stimuli and consid- ered a defensive response that protects the brain from stimulus inundation, which could otherwise lead to cognitive fragmentation and disturbed thought (Braff and Geyer, 1990; Swerdlow et al., 1995). Prepulse inhibition (PPI) is an operational measure of sensorimotor gating; the degree to which the involuntary startle response is inhibited by a weak prepulse reflects the amount of sensorimotor gating. It was found that the age of onset is higher and course of disease is more moderate in females than in males HD patients (Roos et al., 1991; Foroud et al., 1999; Pekmezovic et al., 2007). However, nothing is known about the progression of HD in ovariectomized women. Apoptosis is the prominent form of cell death in chronic neurodegenerative diseases, like HD, where mitochondrial dysfunction and oxidative stress play a major role (Mattson et al., 1995; Kruman et al., 1998; Friedlander, 2003; Johri and Beal, 2012). In addition, microglial activation which is evident early in HD patients, accounts for the release of proinflammatory mediators and further exacerbation of oxidative stress (Tai et al., 2007). These different toxic mechanisms involved in HD pathogenesis including, energy metabolism impairment, inflammatory events and oxida- tive stress are confluent and depend on each other (P erez-de la cruz, and Santamaría, 2007). 3-Nitropropionic acid (3-NPA) is a suicide inhibitor of succinate dehydrogenase that irreversibly inhibits both complex II of electron * Corresponding author. E-mail addresses: abnaim@yahoo.com, abnaim@pharma.asu.edu.eg (A.B. Abdel- Naim). Contents lists available at ScienceDirect Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm http://dx.doi.org/10.1016/j.neuropharm.2016.01.007 0028-3908/© 2016 Elsevier Ltd. All rights reserved. Neuropharmacology 105 (2016) 35e46