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Increased Expression of Annexin A7 in Temporal Lobe Tissue of Patients

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Increased Expression of Annexin A7 in Temporal Lobe Tissue of Patients Histol Histopathol (2011) 26: 571-579 Histology and http://www.hh.um.es Histopathology Cellular and Molecular Biology Increased expression of annexin A7 in temporal lobe tissue of patients with refractory epilepsy Sheng-nian Zhou1*, Cheng-shan Li1*, Li-qing Liu2, Yan Li1, Xue-feng Wang3 and Lan Shen3 1Department of Neurology, Qilu Hospital, Shandong University, Jinan, China, 2Shandong University of Traditional Chinese Medicine, Jinan, China and 3Department of Neurology, the First Affiliated Hospital, Chongqing Medical University, Chongqing, China *Both authors (Sheng-nian Zhou and Cheng-shan Li) contributed equally to the paper Summary. Annexin A7 is a member of the family of with the use of antiepileptic drugs (AEDs). This type of annexins, which are thought to function in the regulation epilepsy is referred to as drug-resistant epilepsy (Regesta of calcium homeostasis and the fusion of vesicles. and Tanganelli, 1999). The pathogenetic mechanisms Refractory epilepsy may be related to the imbalance of underlying epileptic seizures are still poorly understood. calcium homeostasis. Our aims are to investigate the The mechanisms that have been associated with seizure expression of Annexin A7 in epileptic brains in recurrence include the imbalance of calcium homeostasis comparison with human controls and to explore Annexin (DeLorenzo et al., 2005), multi-drug resistance protein A7’s possible role in refractory epilepsy. We examined over-expression (Kwan and Brodie, 2005; Chengyun et the expression of Annexin A7 via immunohisto- al., 2006), axonal sprouting and neurogenesis (Zucchini chemistry, double-label immuno-fluorescence and et al., 2005) and the activity of reactive astrocytes (Jabs western blot. The expression of Annexin A7 was shown et al., 2008; Wetherington et al., 2008). to be significantly increased in patients with refractory Ca2+ signaling has a pivotal role in the regulation of epilepsy. Double-label immunofluorescence and many cellular processes. The regulation of intracellular confocal microscopy disclosed Annexin A7 calcium homeostasis is very complex and includes many immunoreactivity in the neurons, which were recognized proteins, such as Ca2+ channel proteins (Gargus, 2009), by the antibody of neuron specific enolase (NSE). The IP3R (Matsumoto and Nagata, 1999; Missiaen et al., result showed that Annexin A7 may be involved in the 2000), RYR (Sutko and Airey, 1996; Missiaen et al., pathophysiology of refractory epilepsy and may play a 2000) and Anxa7 (Döring et al., 1995; Srivastava et al., role in developing and maintaining the epilepsy. 1999; Herr et al., 2001; Clemen et al., 2003; Watson et al., 2004; Schrickel et al., 2007). Previous research has Key words: Annexin A7, Refractory epilepsy, Calcium explored the relevance of some of these proteins to homeostasis, Pathogenetic mechanisms, Human brain refractory epilepsy; however, there is little evidence or information on the role of Anxa7. Annexin A7 (Anxa7, also called synexin) is a Introduction member of the class of Ca2+- and phospholipid-binding proteins that are characterized by a bipartite structure Epilepsy is a chronic neurological disorder comprised of a variable N-terminal domain and a characterized by recurrent spontaneous seizures that are conserved C-terminal domain of Ca2+- and caused by sudden aberrant neuronal discharge. phospholipid-binding sites. The unique N-terminal Approximately 1% of the world’s population suffers domains are thought to confer functional diversity from epilepsy, which numbers around 9 million patients (Gerke and Moss, 2002). Anxa7, which was the first of in China. It is estimated that approximately 20-30% of this class of proteins to be discovered, is an agent that epileptic patients do not achieve adequate seizure control mediates the aggregation of chromaffin granules and the fusion of membranes and phospholipids in the presence Offprint requests to: Sheng-nian Zhou, Department of Neurology, Qilu of Ca2+-ions (Creutz et al., 1978). Anxa7 has 47-kDa Hospital, Shandong University, Jinan, 250012, China. e-mail: and 51-kDa isoforms that have different N-terminal [email protected] domains and exhibit a tissue-specific expression pattern. 572 Annexin in temporal lobe of epileptic patients The 47-kDa isoform is present in all tissues except for Chongqing University of Medical Sciences. Among skeletal muscle, while the 51-kDa isoform is exclusively them, males: 6, females: 5, age: 13-31years, mean age: present in all tissues. Both isoforms are expressed in the 21.82±6.4years. Table 2 shows the clinical features of heart muscle, brain tissue and red blood cells (Magendzo the control. These samples contained temporal et al., 1991; Selbert et al., 1995; Clemen et al., 1999; neocortical tissue adjacent to the trauma lesions. All Herr et al., 2003). At present, considerable evidence patients were diagnosed by pathology as serious brain supports the view that Anxa7 plays a role in regulating trauma and need to debridement and intracranial intracellular calcium homeostasis (Döring et al., 1995; decompression in order to save life. No patients had Srivastava et al., 1999; Herr et al., 2001; Clemen et al., prior history of seizures, exposure to antiepileptic drugs 2003; Watson et al., 2004; Schrickel et al., 2007) and or other neurologic disorders. The two neuropathologists forming a Ca2+ channel (Pollard et al., 1992). Since the also reviewed these cases. maintenance of intracellular calcium homeostasis is essential for normal brain function, it is conceivable that Tissue Preparation Anxa7 is abnormally expressed in brains of refractory epileptic patients whose maintenance of calcium One part of the resected brain tissue specimen was homeostasis is at risk. immediately placed in a cryovial that had been soaked in To investigate the expression of Anxa7 levels, we buffered DEPC (1:1000) for 24 h and conserved in liquid used immunohistochemistry, western blots and double- nitrogen. This part of the brain was used for Western label immunofluorescence for localization. blot. Other parts were fixed in 10% buffered formalin for 48 hours, embedded in paraffin and sectioned at either 5 Materials and methods µm for immunohistochemistry or 10 um for immuno- fluorescence analysis. These sections were placed on Patient selection polylysine-coated slides. The same process was employed for the brain tissue specimens from the In this study, 38 patients with refractory epilepsy controls. with the typical clinical manifestations and characteristic electroencephalograms were selected at random from Immunohistochemistry 240 patients in our epilepsy brain bank. Among the total, males: 24, females: 14, age: 8-48 years, mean age: All paraffin sections were deparaffinized in xylene, 25.92±10.39 years, duration: 3-39 years, mean duration: rehydrated in graded ethanol, which was perforated by 13.5±7.5 years. the secondary generalized tonic - clonic Triton X-100 (0.4%, for 15 min), and incubated in H2O2 seizure from partial seizure: 16 cases, generalized tonic - (3%) for 10 minutes at room temperature to block clonic seizure: 8 cases, complex partial seizure:10 cases, endogenous peroxidase activity. To retrieve the antigen, multiple seizure type: 2 cases (including simple, the sections were heated in a 10 mmol/l sodium citrate complex partial seizure), simple partial seizure: 1 case, buffer pH6 in a microwave oven for 20 min at 92–98ºC. secondary epilepsy: 1 case. All the brain tissues were The sections were then blocked in normal goat serum for obtained from temporal neocortex. Table 1 summarizes 30 minutes at 37°C to reduce non-specific binding the clinical features as follows. (Zhongshan Gold Bridge Inc., Beijing, China). The Before surgery, informed consent was obtained from sections were subsequently incubated in monoclonal the patients or their relatives for the use of their data and mouse anti-human Anxa7 primary antibody (1:150, BD brain tissues for research. This study was approved by Biosciences, USA) at 4ºC overnight. This was followed the National Institutes of Health and the Committee on by incubation with biotinylated goat anti-mouse Human Research at Chongqing Medical University. secondary antibody for 30 minutes at 37ºC. After Pre-surgical assessment included a detailed history, washing with PBS, sections were treated with avidin- neurological examination, interictal and ictal video-EEG biotin peroxidase complexes for 30 min at 37ºC monitoring, neuropsychological testing and neuro- (Zhongshan Golden Bridge Inc., Beijing, China). radiological studies. Before surgery, each epileptic lesion Immunoreactivity was observed with 3, 30- was localized by 24-h EEG or video-EEG, brain diaminobenzidine (DAB, Zhongshan Gold Bridge Inc., magnetic resonance imaging (MRI) and intraoperative Beijing, China), and subsequent counterstaining was electrocorticography (ECOG). All patients had taken performed with Harris hematoxylin. Negative controls maximal doses of at least three or more antiepileptic were processed by substituting PBS for the primary drugs (AEDs), including phenytoin, valproic acid, antibody. An AX80 microscope (Olympus, Tokyo, carbamaze-pine, phenobarbital, topiramate lamotrigine Japan) was used for photomicrography, and a TC-FY- and traditional Chinese medicine. The diagnosis of the 2050 pathology system (Yuancheng Inc., Beijing, China) seizure type was classified according to the 1981 was used for image acquisition. The quantification of the International Classification of Epilepsy Seizures of the optical densities of every random
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