Neuroscience Letters 594 (2015) 144–149

Contents lists available at ScienceDirect

Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet

Research article

A bout of treadmill exercise increases matrix metalloproteinase-9 activity in the rat hippocampus Takeshi Nishijima ∗ , Masashi Kawakami, Ichiro Kita Laboratory of Behavioral Physiology, Graduate School of Human Health Sciences, Tokyo Metropolitan University, 1-1 Minami-Osawa, Hachioji, Tokyo 192-0397, Japan

h i g h l i g h t s • We examined changes in MMP-9 activity in the rat hippocampus following exercise. • MMP-9 activity in the rat hippocampus was increased 12 h after mild exercise. • MMP-9 might be a new molecular target regulating exercise-induced hippocampal plasticity.

a r t i c l e

i n f o

Article history: Received 29 December 2014 Received in revised form 19 March 2015 Accepted 30 March 2015 Available online 1 April 2015 Keywords: Exercise Hippocampus MMP-9 Gel zymography Extracellular matrix

a b s t r a c t Regular exercise induces a variety of structural changes in the hippocampus of rodents, although the underlying mechanisms remain obscure. Particularly, the possible involvement of molecules regulating the remodeling of the extracellular matrix (ECM) is under-studied. Matrix metalloproteinase-9 (MMP9), an extracellular protease, plays a critical role in regulating neuronal plasticity by remodeling the ECM in the brain. The current study used gel zymography to examine for changes in the proteolytic activity of MMP-9 in the rat hippocampus following a bout of treadmill exercise at mild (10 m/min) or moderate (25 m/min) intensity. We found that MMP-9 activity was significantly increased at 12 h after mild treadmill exercise. However, the activity of MMP-2 and the expression level of the tissue inhibitor of metalloproteinase-1 (TIMP-1) were unchanged following exercise. These findings suggest that exercise triggers MMP-9 activation in the hippocampus, which might be a new molecular mechanism of exercise-induced hippocampal plasticity. © 2015 Elsevier Ireland Ltd. All rights reserved.

1. Introduction The hippocampus, a highly plastic part of the brain, adaptively responds to physical exercise. Previous studies have demonstrated that regular exercise induces a variety of structural changes in the hippocampus, including neurogenesis [17,22,24], synaptogenesis [3], and angiogenesis [23], which possibly contribute to functional improvement such as better spatial learning [2]. However, the molecular mechanisms underlying these exercise-induced structural changes are still unveiled. The central nervous system consists of not only cells, i.e., neurons and glia, but also the extracellular environment, which occupies approximately 20% of the brain volume [20]. In order to

∗ Corresponding author at: Graduate School of Human Health Sciences, Tokyo Metropolitan University, 1-1 Minami-Osawa, Hachioji, Tokyo 192-0397, Japan. Tel.: +81 42 677 2963; fax: +81 42 677 2961. E-mail address: [email protected] (T. Nishijima). http://dx.doi.org/10.1016/j.neulet.2015.03.063 0304-3940/© 2015 Elsevier Ireland Ltd. All rights reserved.

maintain cellular function, proteolytic disassembly and remodeling of the extracellular matrix (ECM) is critical [26]. In the brain, matrix metalloproteinases (MMPs) are a major family of extracellular proteases that play a pivotal role in activity-dependent remodeling of the ECM [5,12]. Therefore, it is possible that MMPs are involved in regulation of the exercise-induced structural changes in the hippocampus. MMP-9, forming a subfamily of gelatinase with MMP-2, is a well-characterized extracellular protease in the brain. MMP-9 is mainly released pericellularly by neurons, though it is released to some extent by glial cells as well [11,13,21]. In most studies, MMP-9 is thought of as a key mediator of pathological manifestations. Ischemia- or kainate-induced excitotoxicity is known to induce remarkable MMP-9 activation in the hippocampus, resulting in neuronal damage [7,8,27]. However, MMP-9 also functions in forms of neuronal plasticity such as long-term potentiation [15,25], neurogenesis [1], dendritic remodeling [21], and hippocampusdependent learning and memory [10,14,15]. Importantly, the proteolytic activity of MMP-9 is controlled by neuronal activity

T. Nishijima et al. / Neuroscience Letters 594 (2015) 144–149

145

[4,11,13]. For example, the enhanced neuronal activity triggered by pentylenetetrazole treatment transiently increases the activity of MMP-9, but not of MMP-2, through NMDA receptor activation in the mouse hippocampus [13]. Since treadmill exercise induces glutamatergic NMDA receptor activation in the rat hippocampus [16], we hypothesized that a bout of treadmill exercise would increase MMP-9 proteolytic activity in the rat hippocampus. To test this hypothesis, we examined temporal changes in the proteolytic activity of MMP-9 in the rat hippocampus following a bout of treadmill exercise. Since hippocampal neuronal activation caused by treadmill exercise is intensity dependent [9,19], rats were subjected to treadmill exercise at either mild (10 m/min) or moderate (25 m/min) speed. The hippocampi were collected at 0, 6, 12, and 24 h after the exercise. The proteolytic activities of MMP-9, as well as of MMP-2, were analyzed by gel zymography. In addition, expression of the tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), an endogenous MMP-9 inhibitor, was also examined.

2. Materials and methods 2.1. Animals Eight-week-old adult male Wistar rats (SLC, Shizuoka, Japan) were housed in groups 3–4 to a cage under controlled conditions of temperature (22–24 ◦ C) and light (12/12-h light/dark cycle, light on at 5:00), and provided food and water ad libitum. All experimental procedures were approved by the Animal Experimental Ethics Committee of the Tokyo Metropolitan University.

2.2. Experimental designs This study consisted of three experiments. First, we validated our gel zymography protocol with kainic acid-induced MMP-9 activation in the hippocampus (Experiment 1). Twenty-four hours after an intraperitoneal injection of saline (n = 2) or kainic acid (10 mg/kg bw; n = 2), rats were deeply anesthetized with pentobarbital sodium and transcardially perfused with cold saline. The hippocampi were quickly dissected out, frozen with liquid nitrogen, and stored at −80 ◦ C. The proteolytic activities of the MMP-9/-2 were analyzed by gel zymography, as described in the following sections. Next, we examined whether the activities of MMP-9/-2 and the expression of TIMP-1 in the hippocampus show diurnal variation (Experiment 2). Rats were sacrificed and their hippocampi collected at 9:00 (n = 6), 15:00 (n = 5), and 21:00 (n = 5), corresponding to what in Experiment 3 would be at 0, 6, and 12 h after treadmill exercise, respectively (Fig. 1A). Finally, we examined temporal changes in hippocampal MMP9/-2 activities and TIMP-1 expression following a bout of treadmill exercise at one of two intensities (Experiment 3). All rats (n = 100) were habituated for 7 days to running in the treadmill apparatus (KN-73, Natsume, Japan) for 30 min/day. During the training session, the exercise speed was gradually increased, so that the rats were able to run at a speed of 25 m/min by the last day. After 4 days of rest to allow the short-term effects of the treadmill habituation procedure to decay, the rats were randomly allocated to three groups: control, mild exercise, and moderate exercise. Rats in mild or moderate groups were subjected to treadmill exercise for 30 min at a speed of 10 or 25 m/min, respectively, speeds below and above the lactate threshold (LT; approximately 20 m/min), a validated physiological index of exercise intensity in rats [18]. Rats in the control group were placed on a stationary treadmill for 30 min. Treadmill exercise was started at 8:30 AM, and the hippocampi were collected at 0, 6, 12, or 24 h after the end of exercise (Fig. 1B).

Fig. 1. Timeline of the experiments. In Experiment 2, rats were sacrificed at 9:00, 15:00, and 21:00 (A). In Experiment 3, rats were randomly subjected to a bout of treadmill exercise at either mild (10 m/min) or moderate (25 m/min) intensity for 30 min. Control rats were placed on a stationary treadmill. Rats were sacrificed 0, 6, 12, and 24 h after exercise (B). Figures in parentheses are the number of rats sacrificed at each time points.

2.3. Tissue preparation The hippocampus from one hemisphere was homogenized in 500 ␮L of lysis buffer (20 mM Tris–HCl pH 7.6, 150 mM NaCl, 5 mM CaCl2 , 1% Triton X-100, 1% glycerol, 500 ␮M PMSF). The lysates were centrifuged for 10 min at 10,000 rpm at 4 ◦ C and supernatants collected. A portion of the supernatant was mixed with additional lysis buffer containing protease inhibitors (Complete Mini, Roche, Germany), and allocated to protein assay and western blotting, whereas the remainder was used for gel zymography without adding protease inhibitors. Protein concentrations were measured with a BCA protein assay kit (Thermo Scientific, USA). 2.4. Gel zymography MMP-9/-2 activities in the hippocampus were measured by gel zymography according to a previous report, with minor modifications [13]. Samples containing 1 mg of protein were incubated with 50% Gelatin Sepharose 4B (GE Healthcare, USA) for 24 h at 4 ◦ C with shaking for MMP-9/-2 extraction. After centrifugation (500 × g, 2 min, 4 ◦ C), the pellets were washed three times with working buffer (50 mM Tris–HCl pH 7.6, 150 mM NaCl, 5 mM CaCl2 , 0.05% Brij 35), then resuspended in 100 ␮L of the working buffer containing 10% DMSO. After a 2-h incubation with shaking, 20 ␮L of the eluates was mixed with 10 ␮L of Laemmli buffer not containing reducing agent, and subjected to electrophoresis without prior boiling on 10% SDS-polyacrylamide gels containing 0.1% gelatin. After washing twice in 2.5% Triton X-100 to remove excess SDS, gels were incubated in Novex® zymogram developing buffer (Invitrogen, USA) for 48 h at 37 ◦ C to allow for enzymatic digestion of gelatin. Then gels were stained with 0.25% Coomassie brilliant blue G-250 (Sigma–Aldrich) for 30 min and de-stained with 10% methanol containing 7% acetic acid. The total gelatinolytic activities including pro-MMPs were densitometrically quantified using Image-J software (NIH).

146

T. Nishijima et al. / Neuroscience Letters 594 (2015) 144–149

2.5. Western blotting for TIMP-1 Standardized amounts of protein were mixed with Laemmli sample buffer containing 0.1% 2-mercaptoethanol and boiled for 10 min. Samples containing 20 ␮g of protein were electrophoresed on 16% SDS-polyacrylamide gels and transferred to PVDF membranes. Nonspecific binding was blocked by preincubating the membranes for 1 h in TBST (20 mM Tris–HCl pH 7.5, 0.5 M NaCl, and 0.05% Tween-20) containing 5% BSA. Following washes with TBST, the membranes were incubated with rabbit anti-TIMP-1 antibody (1:500, SAB4502971, Sigma–Aldrich, USA) in TBST containing 5% BSA overnight at 4 ◦ C. Following washes with TBST, the membranes were incubated with HRP-conjugated anti-rabbit IgG antibody (1:5000 in TBST containing 5% skim milk, NA934, GE Healthcare, UK) for 1 h at room temperature. Protein bands were visualized by incubation with Enhanced Chemiluminescence (Western Lightning Plus-ECL, PerkinElmer) and captured using an Image Quant LAS 4000 mini (GE Healthcare). The membranes were then re-probed with rabbit anti-GAPDH antibody (1:5000 in TBST, #2275, Trevigen, USA) as a loading control. The optical density of the bands was quantified using Image-J and normalized to the level of GAPDH. 2.6. Statistical analysis Proteolytic activities of MMP-9/-2 and protein levels of TIMP-1 were presented as relative changes from the control values (9:00 in Experiment 2, or the non-exercise control at individual time points in Experiment 3). One-way ANOVA followed by Tukey’s post-hoc test was performed to determine the statistical significance of differences between groups at individual time points (Prism 5, MDF Co.). Data were expressed as mean ± SEM. The threshold for statistical significance was set at P < 0.05.

Fig. 2. Representative results of gel zymography of hippocampal homogenates from saline- or kainic acid-treated rats. Kainic acid treatment remarkably increased gelatinolytic activities of both MMP-9 and MMP-2 (left), which were completely blocked when a gel was incubated with developing buffer containing 50 mM EDTA (right).

3.2. Experiment 2: diurnal variation of MMP-9/-2 activity and TIMP-1 expression The design of Experiment 3 that follows is based on the premise that MMP-9/-2 activities and TIMP-1 expression have no diurnal variation. We therefore conducted a pilot study to determine whether MMP-9/-2 activities and TIMP-1 expression are stable in a control, non-exercise condition. As shown in Fig. 3, there were no statistical differences in the activities of MMP-9 (F(2,13) = 0.412, P = 0.671, Fig. 3A), of MMP-2 (F(2,13) = 0.589, P = 0.569, Fig. 3B), or in TIMP-1 expression (F(2,13) = 0.687, P = 0.520, Fig. 3C) among hippocampi obtained at different times of day. These results suggest that MMP-9/-2 activities and TIMP-1 expression do not have diurnal variation, at least at the time points examined in this study.

3. Results 3.1. Experiment 1: validation of gel zymography

3.3. Experiment 3: changes in MMP-9/-2 activities and TIMP-1 expression after a bout of treadmill exercise

A typical gel zymography result with hippocampal homogenates is shown in Fig. 2. We confirmed that two transparent bands (upper, MMP-9; lower, MMP-2) were detectable even in a homogenate from a saline-treated control rat. Both MMP-9 and MMP-2 activities were apparently increased by kainic acid treatment. As expected, these transparent bands were eliminated when the gel was incubated with developing buffer containing 50 mM EDTA, a non-specific metalloproteinase inhibitor.

In MMP-9 activity (Fig. 4A), one-way ANOVA revealed that statistical significance was only found at 12 h after exercise (F(2,22) = 3.748, P < 0.05). Post-hoc testing indicated that only the MMP-9 activity in rats that performed mild-intensity exercise was significantly higher than that in control rats (P < 0.05). Although MMP-9 activity was slightly increased at 6 h (F(2,22) = 2.038, P = 0.154) and 24 h (F(2,22) = 2.115, P = 0.145) after treadmill exercise, it did not reach statistical significance. No significant changes were

Fig. 3. No changes were observed in MMP-9 activity (A), MMP-2 activity (B), or TIMP-1 protein levels (C) in the rat hippocampus across time of day. Data were quantified and presented as relative changes from 9:00 at the individual time points (mean ± SEM, n = 5–6 per group). GAPDH: a reference protein for quantification.

T. Nishijima et al. / Neuroscience Letters 594 (2015) 144–149

147

Fig. 4. Changes in MMP-9 activity (A), MMP-2 activity (B), and TIMP-1 protein levels in the rat hippocampus following a bout of treadmill exercise at either mild (10 m/min) or moderate (25 m/min) intensity. MMP-9 activity was increased 12 h after mild-intensity exercise (A). No changes were observed in MMP-2 (B) or TIMP-1 (C). Data were quantified and presented as relative changes from control at the individual time points (mean ± SEM, n = 8–9 per group). GAPDH: a reference protein for quantification. *P < 0.05 vs control at the individual time points (one-way ANOVA and Tukey’s post hoc tests).

observed in either MMP-2 activity (Fig. 4B) or in TIMP-1 expression (Fig. 4C) at any time point. 4. Discussion Considering the physiological role of MMP-9 in regulating neuronal plasticity, we hypothesized that exercise induces a variety of structural changes in the hippocampus through activity-dependent activation of MMP-9. This study was designed as a first step toward exploring this possibility. MMP-9 activity has been demonstrated to increase several hours to a day after a pharmacological or physiological manipulation in a stimulus-dependent manner [8,13,14,21]. Therefore, we measured MMP-9 activity at different time points following a bout of exercise. In addition, we examined the effect of exercise intensity on MMP-9 activation. Our results demonstrated that treadmill exercise at mild intensity significantly increased MMP-9 activity in the rat hippocampus 12 h later. Although these results must be interpreted cautiously, as discussed below, to the best of our knowledge, this is the first study demonstrating that exercise triggers MMP-9 activation in the hippocampus, which supports in part the above hypothesis. Unlike most of the previous studies of MMP-9, which examined activation under pathological conditions [7,8,13,27], we measured MMP-9 activity in the hippocampus following a bout of

physiological exercise. Indeed, the increase of MMP-9 activity following exercise was limited to about 130% versus non-exercised control (Fig. 4A), which is a considerably smaller effect size than reported in previous studies demonstrating a more than 300% increase after pharmacological treatments or brain ischemia [7,8,13]. This is also apparent in the current study, in that MMP-9 activity in the rat hippocampus was remarkably increased by kainic acid treatment (Fig. 2). We measured MMP-9 proteolytic activity in the hippocampus using the same technique as these previous studies, gel zymography [7,8,13]. Similarly to the previous studies [7,8,13], pro-MMP-9 and active MMP-9 were not discriminated because they may migrate as one band on the gels. Hence, we consider the apparent MMP-9 activity detected in our protocol include any activity contributed by proenzyme. The same limitation applies to MMP-2. What is important is that, compared to other gelatin zymography techniques such as in situ zymography, this assay has a striking advantage in that MMP-9 activity can be measured separately from MMP-2 based on the difference in molecular weight. However, since MMP-9 is predominantly expressed around neuronal cell bodies and dendrites, especially in the granule cell layer of the dentate gyrus (DG) [13,21], gel zymography using whole hippocampal homogenates as performed here obviously leads to an underestimation of the changes in MMP-9 activity in the DG.

148

T. Nishijima et al. / Neuroscience Letters 594 (2015) 144–149

Treadmill running is known to evoke neuronal activation in the rat hippocampus in an intensity-dependent manner [9,19]. However, in this study, intensity dependence of MMP-9 activation was not evident; a significant increase in MMP-9 activity was only found after mild-intensity exercise (Fig. 4A). Previous literature demonstrated that treadmill exercise at moderate speed (25 m/min), just above the LT (approximately 20 m/min), induces activation of the hypothalamus–pituitary–adrenal axis, but not at mild speed (15 m/min) [18]. These findings indicate that exercise performed at an intensity above the LT can be considered a type of stress. Importantly, hippocampal neurogenesis is increased by 2-weeks of mild treadmill exercise, which does not elicit the stress response, but not by moderate to high intensity exercise, possibly due to the negative effects of glucocorticoid (stress hormone) secretion [17]. Thus, effects of exercise on the hippocampus are not monotonically intensity dependent and an involvement of the stress response needs to be considered when exercise intensity exceeds the LT. In the current study, the expression of TIMP-1, an endogenous inhibitor of MMP-9, was not increased by moderate exercise. Therefore, an increase in the glucocorticoid secretion might be a reason why MMP-9 activity following moderate exercise was not higher than that following mild exercise, although this is highly speculative and further research is needed. Considering the above-mentioned limitations and possible stress factors, the results do not mean that MMP-9 activation reaches a peak at 12 h and then returns to the basal level at 24 h after mild-intensity exercise, or that exercise can trigger MMP-9 activation in the hippocampus only if the intensity is mild. Rather, our results suggest the possibility that exercise at both mild and moderate intensity triggers MMP-9 activation, especially in the DG, and that the increase in MMP-9 activity is sustained until 24 h after exercise. The DG is a unique region where drastic structural changes, including neurogenesis and dendritic remodeling, continuously occur, in part, under regulation by MMP-9 [1,21]. Further investigation to examine the spatial profile of MMP-9 activation across hippocampal subfields (CA1, CA3, and DG) following exercise using high-resolution in situ zymography [6], would be intriguing. Although in situ zymography does not discriminate between MMP-9 and MMP-2 activity, the current results demonstrating that MMP-2 activity was unchanged following exercise (Fig. 4B) would simplify interpretation of a future in situ study. 5. Conclusion It is well-recognized that regular exercise induces a variety of structural changes in the hippocampus; however, the involvement of molecules regulating the ECM has been under-studied so far. The current study suggests that a bout of physical exercise increases the proteolytic activity of MMP-9, which is a key mediator of activitydependent remodeling of the ECM. This finding warrants further research delineating a role of MMP-9 as a new molecular target regulating exercise-induced hippocampal plasticity. Conflicts of interest The authors declared no conflicts of interest. Acknowledgements We thank H. Mizoguchi for technical support of gel zymography. This study was supported by a Grant-in-Aid for Young Scientists from the Ministry of Education, Culture, Sports, Science and Technology of Japan to TN (#23700775) and a grant from the Meiji Yasuda Life Foundation of Health and Welfare to TN.

References [1] B.Z. Barkho, A.E. Munoz, X. Li, L. Li, L.A. Cunningham, X. Zhao, Endogenous matrix metalloproteinase (MMP)-3 and MMP-9 promote the differentiation and migration of adult neural progenitor cells in response to chemokines, Stem Cells 26 (2008) 3139–3149. [2] P.J. Clark, W.J. Brzezinska, M.W. Thomas, N.A. Ryzhenko, S.A. Toshkov, J.S. Rhodes, Intact neurogenesis is required for benefits of exercise on spatial memory but not motor performance or contextual fear conditioning in C57BL/6J mice, Neuroscience 155 (2008) 1048–1058. [3] M.O. Dietrich, Z.B. Andrews, T.L. Horvath, Exercise-induced synaptogenesis in the hippocampus is dependent on UCP2-regulated mitochondrial adaptation, J. Neurosci. 28 (2008) 10766–10771. [4] M. Dziembowska, J. Milek, A. Janusz, E. Rejmak, E. Romanowska, T. Gorkiewicz, A. Tiron, C.R. Bramham, L. Kaczmarek, Activity-dependent local translation of matrix metalloproteinase-9, J. Neurosci. 32 (2012) 14538–14547. [5] I.M. Ethell, D.W. Ethell, Matrix metalloproteinases in brain development and remodeling: synaptic functions and targets, J. Neurosci. Res. 85 (2007) 2813–2823. [6] M. Gawlak, T. Gorkiewicz, A. Gorlewicz, F.A. Konopacki, L. Kaczmarek, G.M. Wilczynski, High resolution in situ zymography reveals matrix metalloproteinase activity at glutamatergic synapses, Neuroscience 158 (2009) 167–176. [7] J.Y. Lee, H.E. Lee, S.R. Kang, H.Y. Choi, J.H. Ryu, T.Y. Yune, Fluoxetine inhibits transient global ischemia-induced hippocampal neuronal death and memory impairment by preventing blood-brain barrier disruption, Neuropharmacology 79 (2014) 161–171. [8] S.R. Lee, K. Tsuji, E.H. Lo, Role of matrix metalloproteinases in delayed neuronal damage after transient global cerebral ischemia, J. Neurosci. 24 (2004) 671–678. [9] T.H. Lee, M.H. Jang, M.C. Shin, B.V. Lim, Y.P. Kim, H. Kim, H.H. Choi, K.S. Lee, E.H. Kim, C.J. Kim, Dependence of rat hippocampal c-Fos expression on intensity and duration of exercise, Life Sci. 72 (2003) 1421–1436. [10] S.E. Meighan, P.C. Meighan, P. Choudhury, C.J. Davis, M.L. Olson, P.A. Zornes, J.W. Wright, J.W. Harding, Effects of extracellular matrix-degrading proteases matrix metalloproteinases 3 and 9 on spatial learning and synaptic plasticity, J. Neurochem. 96 (2006) 1227–1241. [11] P. Michaluk, L. Kaczmarek, Matrix metalloproteinase-9 in glutamate-dependent adult brain function and dysfunction, Cell Death Differ. 14 (2007) 1255–1258. [12] E.A. Milward, C. Fitzsimmons, A. Szklarczyk, K. Conant, The matrix metalloproteinases and CNS plasticity: an overview, J. Neuroimmunol. 187 (2007) 9–19. [13] H. Mizoguchi, J. Nakade, M. Tachibana, D. Ibi, E. Someya, H. Koike, H. Kamei, T. Nabeshima, S. Itohara, K. Takuma, M. Sawada, J. Sato, K. Yamada, Matrix metalloproteinase-9 contributes to kindled seizure development in pentylenetetrazole-treated mice by converting pro-BDNF to mature BDNF in the hippocampus, J. Neurosci. 31 (2011) 12963–12971. [14] V. Nagy, O. Bozdagi, G.W. Huntley, The extracellular protease matrix metalloproteinase-9 is activated by inhibitory avoidance learning and required for long-term memory, Learn Mem. 14 (2007) 655–664. [15] V. Nagy, O. Bozdagi, A. Matynia, M. Balcerzyk, P. Okulski, J. Dzwonek, R.M. Costa, A.J. Silva, L. Kaczmarek, G.W. Huntley, Matrix metalloproteinase-9 is required for hippocampal late-phase long-term potentiation and memory, J. Neurosci. 26 (2006) 1923–1934. [16] T. Nishijima, M. Okamoto, T. Matsui, I. Kita, H. Soya, Hippocampal functional hyperemia mediated by NMDA receptor/NO signaling in rats during mild exercise, J. Appl. Physiol. (1985) 112 (2012) 197–203. [17] M. Okamoto, Y. Hojo, K. Inoue, T. Matsui, S. Kawato, B.S. McEwen, H. Soya, Mild exercise increases dihydrotestosterone in hippocampus providing evidence for androgenic mediation of neurogenesis, Proc. Natl. Acad. Sci. U. S. A. 109 (2012) 13100–13105. [18] H. Soya, A. Mukai, C.C. Deocaris, N. Ohiwa, H. Chang, T. Nishijima, T. Fujikawa, K. Togashi, T. Saito, Threshold-like pattern of neuronal activation in the hypothalamus during treadmill running: establishment of a minimum running stress (MRS) rat model, Neurosci. Res. 58 (2007) 341–348. [19] H. Soya, T. Nakamura, C.C. Deocaris, A. Kimpara, M. Iimura, T. Fujikawa, H. Chang, B.S. McEwen, T. Nishijima, BDNF induction with mild exercise in the rat hippocampus, Biochem. Biophys. Res. Commun. 358 (2007) 961–967. [20] E. Sykova, C. Nicholson, Diffusion in brain extracellular space, Physiol. Rev. 88 (2008) 1277–1340. [21] A. Szklarczyk, J. Lapinska, M. Rylski, R.D. McKay, L. Kaczmarek, Matrix metalloproteinase-9 undergoes expression and activation during dendritic remodeling in adult hippocampus, J. Neurosci. 22 (2002) 920–930. [22] J.L. Trejo, E. Carro, I. Torres-Aleman, Circulating insulin-like growth factor I mediates exercise-induced increases in the number of new neurons in the adult hippocampus, J. Neurosci. 21 (2001) 1628–1634. [23] K. Van der Borght, D.E. Kobor-Nyakas, K. Klauke, B.J. Eggen, C. Nyakas, E.A. Van der Zee, P. Meerlo, Physical exercise leads to rapid adaptations in hippocampal vasculature: temporal dynamics and relationship to cell proliferation and neurogenesis, Hippocampus 19 (2009) 928–936. [24] H. van Praag, G. Kempermann, F.H. Gage, Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus, Nat. Neurosci. 2 (1999) 266–270.

T. Nishijima et al. / Neuroscience Letters 594 (2015) 144–149 [25] X.B. Wang, O. Bozdagi, J.S. Nikitczuk, Z.W. Zhai, Q. Zhou, G.W. Huntley, Extracellular proteolysis by matrix metalloproteinase-9 drives dendritic spine enlargement and long-term potentiation coordinately, P. Natl. Acad. Sci. U. S. A. 105 (2008) 19520–19525. [26] Z. Werb, ECM and cell surface proteolysis: regulating cellular ecology, Cell 91 (1997) 439–442.

[27] J.W. Zhang, S. Deb, P.E. Gottschall, Regional and differential expression of gelatinases in rat brain after systemic kainic acid or bicuculline administration, Eur. J. Neurosci. 10 (1998) 3358–3368.

149

A bout of treadmill exercise increases matrix metalloproteinase-9 activity in the rat hippocampus.

Regular exercise induces a variety of structural changes in the hippocampus of rodents, although the underlying mechanisms remain obscure. Particularl...
804KB Sizes 0 Downloads 9 Views