Open Access

Effect of treadmill exercise on spatial navigation impairment associated with cerebellar Purkinje cell loss following chronic cerebral hypoperfusion

  • Authors:
    • Jae‑Min Lee
    • Chang‑Ju Kim
    • Jong‑Min Park
    • Min Kyung Song
    • Youn‑Jung Kim
  • View Affiliations

  • Published online on: April 19, 2018     https://doi.org/10.3892/mmr.2018.8893
  • Pages: 8121-8128
  • Copyright: © Lee et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

In addition to roles in motor coordination, the cerebellum is also associated with cognitive function. The aim of the present study was to investigate the effect of treadmill exercise on spatial navigation deficit induced by chronic cerebral hypoperfusion (CCH). Furthermore, whether decreased loss of Purkinje cells, which contain the calcium‑binding protein in the posterior lobe of the cerebellum, attenuates the spatial navigation deficit induced by CCH was also investigated. Wistar rats were randomly divided into three groups: Sham group, bilateral common carotid arteries occlusion (BCCAO) group and a BCCAO + exercise (Ex) group. The rats in the BCCAO + Ex group ran on a treadmill for 30 min once a day for 8 weeks, starting at 4 weeks post‑birth. CCH was induced by performing BCCAO at 12 weeks post‑birth. The Morris water maze test was performed to determine the spatial navigation function of the rats. To investigate the histological features of the cerebellum in all of the experimental groups post‑treatment, terminal deoxynucleotidyl transferase dUTP nick end labeling staining, as well as immunohistochemical analysis revealing the expression of calbindin, parvalbumin, glial fibrillary acidic protein, ionized calcium‑binding adaptor molecule 1 and caspase‑3, was performed. The results of the present study revealed that treadmill exercise improved spatial navigation, decreased the expression of reactive astrocytes and microglial cells, and decreased apoptotic rates in the cerebellar vermis post‑CCH. Treadmill exercise also attenuated the loss of Purkinje cells following CCH. The number of Purkinje cells was revealed to be negatively correlated with spatial navigation performance. These results indicate that treadmill exercise may attenuate spatial navigation impairment via inhibition of Purkinje cell loss in the posterior lobe of the cerebellum following CCH. Therefore, treadmill exercise may represent a therapeutic strategy for the treatment of patients with spatial navigation impairment following CCH.

Introduction

The role of the cerebellum was previously considered to be confined to movement, along with the cortex and basal ganglia; however, it has recently been redefined to represent a broader area of functions, including cognitive functions (1,2). The cerebellum receives and sends information from various brain regions, including the hypothalamus, hippocampus and cortex (3). The function of the cerebellum is strongly associated with the hippocampus, and the cerebellum has been revealed to affect hippocampal activity, including spatial navigation and working memory (35). Although it has not been fully determined, the cerebellum may affect the hippocampus in two ways (1). The cerebellar brain region is primarily associated with cognitive functioning, particularly spatial navigation and executive tasks, and is located in the posterior lobe of the cerebellum. A previous neuroimaging study has demonstrated that cognitive functions are associated with the posterior lobe of the cerebellum (6). Damage to the posterior lobe of the cerebellum has been revealed to be associated with impairment of spatial working memory, and transgenic mice with cerebellar dysfunction have been demonstrated to exhibit spatial navigation deficit (7,8).

Rats with Purkinje cells removed in the cerebellum exhibited impaired spatial navigation performance following analysis using the rotor-rod and Morris water maze tests (9). Purkinje cells are located the Purkinje layer of the cerebellum, which exhibits the greatest abundance of calcium-binding proteins in the cerebellum, such as calbindin D28k and parvalbumin. Such proteins have important roles in physiological processes, including cell cycle regulation, muscle contraction and the regulation of intracellular Ca2+ concentration associated with apoptosis (10). Purkinje cells, which have important roles in cerebellar function, are particularly vulnerable to damage in ischemia (11). Purkinje cell death induced by ischemia in the cerebellum has been reported to be induced by excitotoxicity due to glutamate release and intracellular calcium (12).

Chronic cerebral hypoperfusion (CCH) is a major pathological feature of vascular dementia that results in progressive cognitive impairment due to interference in the circulatory system (1315). CCH has been demonstrated to induce hypoxia and oxidative stress, as well as cause inflammation of the cerebral cortex, white matter, hippocampus and striatum, resulting in impaired cognitive function (1619). However, the pathological mechanism of CCH has not been fully determined. Research concerning the effects of CCH on the cerebellum and determining novel therapeutic strategies to enhance spatial navigation of patients suffering from CCH has been limited.

Treadmill exercise has been demonstrated to ameliorate neurological impairments following various brain disorders, including ischemia and Alzheimer's disease (20,21). Treadmill exercise has also been revealed to improve cognitive function by reducing the apoptosis rate of neurons and the reactivity of astrocytes in the cerebellum following transient global ischemia (22), and also protect against age-associated Purkinje cell loss (23). The aim of the present study was to investigate whether CCH induces a loss of Purkinje cells, and to investigate the effect of treadmill exercise on spatial navigation impairment associated with CCH.

Materials and methods

Experimental animals

Male Wistar rats (n=30; weight 80±10 g, 3-weeks old, Orient Bio, Inc., Seongnam, Korea) were used in the present study. The rats were housed under controlled temperature (20±2°C), humidity (60±5%), and lighting conditions (7:00 a.m. to 7:00 p.m.) with food and water available ad libitum. All animal experimental procedures conformed to the regulations stipulated by the National Institutes of Health (Bethesda, MD, USA) (24) and the guidelines of the Korean Academy of Medical Science (Seoul, Korea). The present study was approved by the Kyung Hee University Institutional Animal Care and Use Committee [Seoul, Korea; KHUASP (SE)-16-149]. The rats were randomly divided into three groups: Sham group (n=10), bilateral common carotid arteries occlusion (BCCAO) group (n=10) and a BCCAO + treadmill exercise (BCCAO + Ex) group (n=10).

Treadmill exercise protocol

The rats in the BCCAO + Ex group were made to run on a treadmill for 30 min once a day for 8 weeks starting at 4 weeks post-birth, according to a previously described method (21). The treadmill exercise load consisted of running at 2 m/min for the first 5 min, 3 m/min for the following 5 min and 5 m/min for the last 20 min, at 0 degrees of inclination. The rats in the non-exercise groups were placed on the treadmill without being made to run for the same time period as the exercise group.

BCCAO

Rats were anesthetized via subcutaneous injection of 250 mg/kg tribromoethanol (Avertin®; Sigma-Aldrich; Merck KGaA, Darmstadt, Germany). BCCAO was performed to induce CCH and was performed carefully to avoid damage to the vagus nerve and surrounding tissues. Both carotid arteries were exposed by a ventral midline incision and double ligated with 3-0 silk (Ailee, Seoul, Korea) immediately below the carotid bifurcation. The rats in the sham group underwent the same operation procedure without vessel ligation.

Open field test

Activity was determined using the open field test. As a previously described method (25), the rats were randomly assigned to an order of testing and placed in a white square open-field arena (100×100 cm) made of wood, enclosed by 40-cm-high walls and exposed to strong illumination (200 lux). The arena was divided into 25 squares (20×20 cm), consisting of 9 central and 16 peripheral squares. The rats were placed in the center of the arena and were allowed to explore the environment for 1 min. Following this time, the number of squares crossed was recorded for 5 min.

Morris water maze test

In order to investigate the spatial navigation in rats, the latency time in the Morris water maze test was determined according to a previously described method (1). The Morris water maze test consisted of a circular pool (painted white, 200 cm diameter, 60 cm high) filled with water (22±2°C, 37 cm deep) that was made opaque by the addition 1 kg skim milk powder. A platform (15 cm diameter, 35 cm high) was submersed 2 cm below the water surface in one of four quadrants in the pool. A video recorder was hung from the ceiling and was connected to a tracking device (SMART; Panlab, Barcelona, Spain). The animals were subjected to three trials per session. In each session, the rats were permitted to search for the platform for 60 sec. If the rat located the platform, the animals were permitted to remain on the platform for a further 10 sec. If the rat did not locate the platform within 60 sec, the rat was guided to the platform and permitted to remain for a further 10 sec. The latency times taken to locate the submerged platform were recorded. The animals were tested in this way for a total of 4 days with 3 trials per day.

Immunohistochemistry

A total of 6 animals per group were used for immunohistochemistry staining. Serial sagittal sections (40 µm) were obtained using a freezing microtome (−20 to −25°C; Leica Microsystems GmbH, Wetzlar, Germany). Immunohistochemistry was performed to investigate the expression of glial fibrillary acidic protein (GFAP), ionized calcium-binding adaptor molecule 1 (Iba-1), calbindin D28k and parvalbumin in each cerebellar vermis. Free-floating sections were initially incubated in 3% H2O2 for 30 min at room temperature. Following this, the sections were incubated in blocking solution (1% bovine serum albumin and 0.2% Triton X-100; Vector Laboratories, Inc., Burlingame, CA, USA) for 2 h at room temperature (27°C). The sections were subsequently incubated overnight with the following primary antibodies: GFAP (1:500; AB5804; Chemicon; Merck KGaA), Iba-1 (1:500; ab178846; Abcam, Cambridge, UK), calbindin D28k (1:500; ab11426; Abcam), parvalbumin (1:1,000; ab11427; Abcam), and caspase-3 (1:500; sc-56053; Santa Cruz Biotechnology, Inc., Dallas, TX, USA) overnight at 4°C. Following this, sections were incubated with biotinylated mouse (BA-2000), goat (BA-9500) and rabbit (BA-1100) secondary antibodies (1:200; Vector Laboratories, Inc., Burlingame, CA, USA) for 1 h at room temperature (27°C). The sections were then incubated with an avidin-biotin-peroxidase complex (1:1,000; Vector Laboratories, Inc.) for 1 h at room temperature (27°C). For staining, the sections were incubated in a solution consisting of 0.02% DAB and 0.03% H2O2 in 50 mM Tris-HCl (pH 7.6) for approximately 5 min, following which they were washed with PBS and mounted onto gelatin-coated slides. Cover slips were mounted using Permount® (Fisher Scientific). Sections were assessed in a quantitative fashion, according to a micro-densitometrical method based on optical density using Image Pro® Plus software version 6.0 (Media Cybernetics, Bethesda, MD, USA). The number of positive cells per section was counted in 5 random fields from every specimen with a Nikon Eclipse 80i microscope (magnification, ×40; Nikon Corporation, Tokyo, Japan).

Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining

To visualize DNA fragmentation, which is a marker of apoptosis, TUNEL staining was performed using an in Situ Cell Death Detection kit with fluorescein (Roche Diagnostics GmbH, Mannheim, Germany). Serial sagittal brain sections (40 µm) were fixed in 4% paraformaldehyde at room temperature for 15 min, post-fixed in ethanol-acetic acid (2:1) for 5 min at −20°C and then rinsed with PBS. Following this, sections were incubated with proteinase K (100 µg/ml), rinsed with PBS and incubated in 3% H2O2 for 30 min at room temperature (27°C). Sections were subsequently permeabilized using 0.5% Triton X-100 for 1 h at room temperature (27°C), rinsed again and incubated in the TUNEL reaction mixture for 1 h at 37°C. The sections were rinsed and visualized using a Converter-POD for 1 h in a humidified 37°C chamber. The sections were incubated in a solution containing in 50 mM Tris-HCl (pH 7.6) containing 0.03% DAB, 40 mg/ml nickel chloride, and 0.03% hydrogen peroxide. The slides were counterstained with Nissl staining and mounted onto a gelatin coated slide. The slides were coverslipped with Permount® (Thermo Fisher Scientific, Inc., Waltham, MA, USA).

Statistical analysis

Data are presented as the mean ± standard error of the mean. SPSS software version 23.0 (IBM Corp., Armonk, NY, USA) was used for statistical analysis. Statistical analysis was performed using one-way analysis followed by Tukey's post-hoc test or Pearson's correlation analysis. P<0.05 was considered to indicate a statistically significant with 3–6 independent experiments.

Results

Treadmill exercise alleviates spatial navigation impairment induced by CCH

The Morris water maze test was performed to investigate the effect of treadmill exercise on spatial navigation impairment induced by CCH. The results indicated that the BCCAO group demonstrated an increased escape latency time compared with the sham group (P<0.05; Fig. 1). However, the BCCAO + Ex group demonstrated a significantly shorter escape latency time compared with the BCCAO group on days 3 and 4 of testing (P<0.05; Fig. 1).

Treadmill exercise reduces levels of reactive astrocytes and microglial activation in the cerebellum

To investigate the effect of treadmill exercise on glial cell activation, immunohistochemistry was performed. Photomicrographs of GFAP- and Iba-1-positive cells in the posterior regions of the cerebellar vermis are presented in Fig. 2. GFAP, a marker of reactive astrocytes, was revealed to be significantly increased following cerebral ischemia (26); however, this effect was significantly attenuated following treadmill exercise (P<0.001; Fig. 2A). Iba-1 is a specific marker of microglia. Following transient focal cerebral ischemia induced by BCCAO, Iba-1 expression was demonstrated to be significantly increased in the BCCAO group compared with the sham group. However, this effect was significantly attenuated following treadmill exercise (P<0.001; Fig. 2B).

Treadmill exercise reduces apoptotic cell death in the cerebellum

Apoptotic neuronal cell death was determined via TUNEL analysis, which detects DNA fragmentation (27). The results demonstrated that the BCCAO + Ex group exhibited a significantly decreased number of TUNEL-positive cells in the posterior region compared with the BCCAO group (P<0.001; Fig. 3).

Caspase-3, a member of the caspase family, has an important function in apoptotic cell death (28). The BCCAO + Ex group demonstrated a significantly decreased number of caspase-3-positive cells in the posterior region compared with the BCCAO group (P<0.001; Fig. 3). Furthermore, the BCCAO group demonstrated increased TUNEL and caspase-3-positive cells in the granular and molecular layers of the cerebellar vermis compared with the sham group (Fig. 3).

Treadmill exercise attenuates the loss of Purkinje cells in the cerebellum

Calbindin D28k has regulatory roles in motor coordination, sensory integration and important functions of Purkinje cells (29). The BCCAO + Ex group demonstrated a significantly increased number of calbindin-positive Purkinje cells in the posterior regions compared with the BCCAO group (P<0.001; Fig. 4A). However, calbindin D28k-positive Purkinje cells did not demonstrate a correlation with the latency time in the Morris water maze test (r=−0.278, P=0.316; Fig. 4B).

Parvalbumin, a small protein that is involved in Ca2+ signaling, protects neurons from cell death via suppression of intracellular Ca2+ concentrations (29). The BCCAO + Ex group demonstrated a significantly higher number of parvalbumin-positive Purkinje cells in the posterior region compared with the BCCAO group (P<0.001; Fig. 4A). Furthermore, the number of parvalbumin-positive Purkinje cells was revealed to be negatively correlated with the latency time in the Morris water maze test (r=−0.561, P=0.030; Fig. 4B).

Discussion

Physical exercise has numerous positive effects on brain functions, and running exercises have been revealed to improve various neurodegenerative disorders, such as ischemia, Alzheimer's and Parkinson's disease (20,30,31). In the present study, a low-intensity form of treadmill exercise was employed. The low intensity exercise used in the present study represents ~50–60% of maximum oxygen uptake (32). Previous studies have demonstrated that low-intensity treadmill exercise induced positive effects on neurogenesis in the hippocampal dentate gyrus as well as the recovery of cognitive function in stroke models (33,34). The present study was performed to investigate the effect of treadmill exercise on spatial navigation impairment associated with cerebellar Purkinje cell loss following CCH. The results revealed that treadmill exercise significantly ameliorated the spatial navigation performance of rats in the Morris water maze following CCH. This result is consistent with previous studies, which demonstrated that treadmill exercise alleviated spatial navigation impairment in the radial 8 arm maze and Morris water maze (31,35). Thus, the results of the present study indicate that treadmill exercise may attenuate spatial navigation performance following CCH.

Animal activity by open field test was investigated in the present study (data not shown). The results demonstrated that the activity score in the open field test was not significantly different among the different experimental groups. The present study did not include a sham + Ex group, so it is difficult to expect the effect of exercise in normal group. Heo et al (21) previously revealed that treadmill exercise in normal mice did not exhibit a significant effect on short-term memory. Furthermore, an additional study demonstrated that the number of incorrect choices made in a radial 8-arm maze test by rats in a sham + Ex group was not decreased compared with the sham group (36). The present study investigated whether involuntary exercise attenuates spatial navigation impairment via inhibition of Purkinje cell loss in the cerebellum following CCH. Therefore, a sham + Ex group was not deemed necessary for inclusion in the study design.

Reactive astrocytes and microglia activation following brain injury enhance neuronal death (37,38). Reactive astrocytes result in neuroinflammation, neurotoxic function and the formation of a glial scar (39). Activation of microglial cells, the resident immune cells of the central nervous system, is an important factor involved in central nervous system injury responses and neuronal cell death (38). The results of the present study revealed that treadmill exercise decreased the levels of reactive astrocytes, and activation of microglial cells in the posterior lobe of the cerebellum are consistent with previous studies (40,41). Reactive astrocytes following brain damage have previously been demonstrated to result in increased GFAP expression in neurodegenerative diseases, such as Alzheimer's disease and ischemia (41). Activated microglial cells have been implicated in neuronal apoptosis following ischemic stroke, and enhanced expression of Iba-1 has previously been revealed to be upregulated following transient middle cerebral artery occlusion (27). Therefore, the suppression of reactive astrocytes and microglia activation may represent the underlying neuroprotective effect of treadmill exercise against neuronal damage in the posterior lobe of the cerebellum.

Several studies have demonstrated that cerebral ischemia animal models exhibit increased apoptotic cell death in the brain (28,42). TUNEL and caspase-3-positive cells have also been revealed to be increased in ischemic brains (38). In the present study, treadmill exercise significantly decreased the levels of TUNEL- and caspase-3-positive cells in the posterior region of the cerebellum. Marques-Aleixo et al (43) revealed that a rat treadmill endurance training group demonstrated significantly increased expression levels of the anti-apoptotic protein Bcl-2 in the cerebellum compared with the expression levels exhibited by the sedentary group. A further study revealed that treadmill exercise reduced the rate of apoptosis in the cerebellums of autistic rats (44). The results of the present study indicated that treadmill exercise significantly decreased apoptosis in the cerebellum of rats suffering from CCH and may have a role in attenuating the loss of Purkinje cells.

Intracellular Ca2+ in neurons is important for neural excitability, as calcium enters Purkinje cells during action potentials following activation of voltage-gated Ca2+ channels (45). Cerebral ischemia is reported to induce an increase in intracellular Ca2+ levels, which subsequently results in a marked increase in the activation of proteases, thus resulting in apoptotic cell death (46). Calbindin D28k and parvalbumin regulate motor coordination and sensory integration, which represent important functions of Purkinje cells (47). Thus, the regulation of intracellular Ca2+ levels by calcium-binding proteins is important for the neuronal viability in the brain (10). The results of the present study demonstrated that treadmill exercise significantly attenuated the loss of calbindin D28k- and parvalbumin-positive Purkinje cells following CCH. These results are consistent with a previous study that revealed that treadmill exercise attenuated the loss of calbindin D28k-positive Purkinje cells in the cerebellar vermis of rats suffering from amyloid β25-35-induced Alzheimer's disease (41). Investigation into whether there was a correlation between loss of Purkinje cells and cognitive impairment revealed that there was a significant negative correlation between the number of parvalbumin-positive Purkinje cells and spatial navigation ability. Furthermore, a marginal negative correlation was demonstrated between the number of calbindin D28k-positive Purkinje cells and spatial navigation ability, though this correlation was not significant. Consistent with these observations, a previous study investigated loss of Purkinje cells in the cerebellum by administration of OX7-saporin, and the results revealed that rats exhibited an impaired spatial navigation performance in the Morris water maze test compared with the control group (48). Thus, the results of the present study indicated that treadmill exercise decreased the loss of the Purkinje cells in the cerebellum following CCH in rats and that a negative correlation may exist between loss of Purkinje cells and spatial navigation performance.

In conclusion, the results of the present study indicate that treadmill exercise may exert a neuroprotective effect against the loss of Purkinje cells via the suppression of glial cells and apoptosis. Therefore, treadmill exercise may have potential as a therapeutic intervention strategy for the attenuation of memory impairment in patients with CCH.

Acknowledgements

Not applicable.

Funding

This present study was supported by National Research Foundation of Korea, which was funded by the Ministry of Education, Science and Technology (Seoul, Korea; grant no. NRF-2017R1A2B4012775).

Availability of data and materials

The analyzed data sets generated during the study are available from the corresponding author on reasonable request.

Authors' contributions

JL, JP and YK designed the experiments and the study. JL and MS looked after the animals and performed the experiments. CK participated in designing and discussing the study. JL, JP and YK wrote the manuscript. All authors read and approved the final manuscript.

Ethics approval and consent to participate

The present study was approved by the Kyung Hee University Institutional Animal Care and Use Committee [Seoul, Korea; KHUASP (SE)-16-149].

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References

1 

Rochefort C, Lefort J and Rondi-Reig L: The cerebellum: A new key structure in the navigation system. Front Neural Circuits. 7:352013. View Article : Google Scholar : PubMed/NCBI

2 

Taylor JA and Ivry RB: Cerebellar and prefrontal cortex contributions to adaptation, strategies, and reinforcement learning. Prog Brain Res. 210:217–253. 2014. View Article : Google Scholar : PubMed/NCBI

3 

Yu W and Krook-Magnuson E: Cognitive collaborations: Bidirectional functional connectivity between the cerebellum and the hippocampus. Front Syst Neurosci. 9:1772015. View Article : Google Scholar : PubMed/NCBI

4 

Onuki Y, Van Someren EJ, De Zeeuw CI and Van der Werf YD: Hippocampal-cerebellar interaction during spatio-temporal prediction. Cereb Cortex. 25:313–321. 2015. View Article : Google Scholar : PubMed/NCBI

5 

Lalonde R and Botez MI: The cerebellum and learning processes in animals. Brain Res Brain Res Rev. 15:325–332. 1990. View Article : Google Scholar : PubMed/NCBI

6 

Stoodley CJ and Schmahmann JD: Functional topography in the human cerebellum: A meta-analysis of neuroimaging studies. Neuroimage. 44:489–501. 2009. View Article : Google Scholar : PubMed/NCBI

7 

Burguière E, Arleo A, Hojjati Mr, Elgersma Y, De Zeeuw CI, Berthoz A and Rondi-Reig L: Spatial navigation impairment in mice lacking cerebellar LTD: A motor adaptation deficit? Nat Neurosci. 8:1292–1294. 2005. View Article : Google Scholar : PubMed/NCBI

8 

Tomlinson SP, Davis NJ, Morgan HM and Bracewell RM: Cerebellar contributions to spatial memory. Neurosci Lett. 578:182–186. 2014. View Article : Google Scholar : PubMed/NCBI

9 

Martin LA, Goldowitz D and Mittleman G: The cerebellum and spatial ability: Dissection of motor and cognitive components with a mouse model system. Eur J Neurosci. 18:2002–2010. 2003. View Article : Google Scholar : PubMed/NCBI

10 

Zhao S, Chen N, Yang Z, Huang L, Zhu Y, Guan S, Chen Q and Wang JH: Ischemia deteriorates the spike encoding of rat cerebellar Purkinje cells by raising intracellular Ca2+. Biochem Biophys Res Commun. 366:401–407. 2008. View Article : Google Scholar : PubMed/NCBI

11 

Kelley MH, Taguchi N, Ardeshiri A, Kuroiwa M, Hurn PD, Traystman RJ and Herson PS: Ischemic insult to cerebellar Purkinje cells causes diminished GABAA receptor function and allopregnanolone neuroprotection is associated with GABAA receptor stabilization. J Neurochem. 107:668–678. 2008. View Article : Google Scholar : PubMed/NCBI

12 

Welsh JP, Yuen G, Placantonakis DG, Vu TQ, Haiss F, O'Hearn E, Molliver ME and Aicher SA: Why do purkinje cells die so easily after global brain ischemia? Aldolase C, EAAT4, and the cerebellar contribution to posthypoxic myoclonus. Adv Neurol. 89:331–359. 2002.PubMed/NCBI

13 

Román GC, Erkinjuntti T, Wallin A, Pantoni L and Chui HC: Subcortical ischaemic vascular dementia. Lancet Neurol. 1:426–436. 2002. View Article : Google Scholar : PubMed/NCBI

14 

O'Brien JT, Erkinjuntti T, Reisberg B, Roman G, Sawada T, Pantoni L, Bowler JV, Ballard C, DeCarli C, Gorelick PB, et al: Vascular cognitive impairment. Lancet Neurol. 2:89–98. 2003. View Article : Google Scholar : PubMed/NCBI

15 

Kalaria RN, Maestre GE, Arizaga R, Friedland RP, Galasko D, Hall K, Luchsinger JA, Ogunniyi A, Perry EK, Potocnik F, et al: Alzheimer's disease and vascular dementia in developing countries: Prevalence, management, and risk factors. Lancet Neurol. 7:812–826. 2008. View Article : Google Scholar : PubMed/NCBI

16 

Schmidt-Kastner R, Aguirre-Chen C, Saul I, Yick L, Hamasaki D, Busto R and Ginsberg MD: Astrocytes react to oligemia in the forebrain induced by chronic bilateral common carotid artery occlusion in rats. Brain Res. 1052:28–39. 2005. View Article : Google Scholar : PubMed/NCBI

17 

Jing Z, Shi C, Zhu L, Xiang Y, Chen P, Xiong Z, Li W, Ruan Y and Huang L: Chronic cerebral hypoperfusion induces vascular plasticity and hemodynamics but also neuronal degeneration and cognitive impairment. J Cereb Blood Flow Metab. 35:1249–1259. 2015. View Article : Google Scholar : PubMed/NCBI

18 

Kim SK, Cho KO and Kim SY: White matter damage and hippocampal neurodegeneration induced by permanent bilateral occlusion of common carotid artery in the rat: Comparison between Wistar and Sprague-Dawley strain. Korean J Physiol Pharmacol. 12:89–94. 2008. View Article : Google Scholar : PubMed/NCBI

19 

Hai J, Wan JF, Lin Q, Wang F, Zhang L, Li H, Zhang L, Chen YY and Lu Y: Cognitive dysfunction induced by chronic cerebral hypoperfusion in a rat model associated with arteriovenous malformations. Brain Res. 1301:80–88. 2009. View Article : Google Scholar : PubMed/NCBI

20 

Baek SS and Kim SH: Treadmill exercise ameliorates symptoms of Alzheimer disease through suppressing microglial activation-induced apoptosis in rats. J Exerc Rehabil. 12:526–534. 2016. View Article : Google Scholar : PubMed/NCBI

21 

Heo YM, Shin MS, Kim SH, Kim TW, Baek SB and Baek SS: Treadmill exercise ameliorates disturbance of spatial learning ability in scopolamine-induced amnesia rats. J Exerc Rehabil. 10:155–161. 2014. View Article : Google Scholar : PubMed/NCBI

22 

Seo TB, Kim BK, Ko IG, Kim DH, Shin MS, Kim CJ, Yoon JH and Kim H: Effect of treadmill exercise on Purkinje cell loss and astrocytic reaction in the cerebellum after traumatic brain injury. Neurosci Lett. 481:178–182. 2010. View Article : Google Scholar : PubMed/NCBI

23 

Larsen JO, Skalicky M and Viidik A: Does long-term physical exercise counteract age-related Purkinje cell loss? A stereological study of rat cerebellum. J Comp Neurol. 428:213–222. 2000. View Article : Google Scholar : PubMed/NCBI

24 

National Research Council: Guide for the care and use of laboratory animals. National Academies Press; Washington DC: 2010

25 

Shin MS, Park SS, Lee JM, Kim TW and Kim YP: Treadmill exercise improves depression-like symptoms by enhancing serotonergic function through upregulation of 5-HT1A expression in the olfactory bulbectomized rats. J Exerc Rehabil. 13:36–42. 2017. View Article : Google Scholar : PubMed/NCBI

26 

Zhang Y, Cao RY, Jia X, Li Q, Qiao L, Yan G and Yang J: Treadmill exercise promotes neuroprotection against cerebral ischemia-reperfusion injury via downregulation of pro-inflammatory mediators. Neuropsychiatr Dis Treat. 12:3161–3173. 2016. View Article : Google Scholar : PubMed/NCBI

27 

Cho YS, Shin MS, Ko IG, Kim SE, Kim CJ, Sung YH, Yoon HS and Lee BJ: Ulinastatin inhibits cerebral ischemia-induced apoptosis in the hippocampus of gerbils. Mol Med Rep. 12:1796–1802. 2015. View Article : Google Scholar : PubMed/NCBI

28 

Shin MS, Ko IG, Kim SE, Kim BK, Kim TS, Lee SH, Hwang DS, Kim CJ, Park JK and Lim BV: Treadmill exercise ameliorates symptoms of methimazole-induced hypothyroidism through enhancing neurogenesis and suppressing apoptosis in the hippocampus of rat pups. Int J Dev Neurosci. 31:214–223. 2013. View Article : Google Scholar : PubMed/NCBI

29 

Celio MR: Calbindin D-28k and parvalbumin in the rat nervous system. Neuroscience. 35:375–475. 1990. View Article : Google Scholar : PubMed/NCBI

30 

Cotman CW and Berchtold NC: Exercise: A behavioral intervention to enhance brain health and plasticity. Trends Neurosci. 25:295–301. 2002. View Article : Google Scholar : PubMed/NCBI

31 

Lee JM, Park JM, Song MK, Oh YJ, Kim CJ and Kim YJ: The ameliorative effects of exercise on cognitive impairment and white matter injury from blood-brain barrier disruption induced by chronic cerebral hypoperfusion in adolescent rats. Neurosci Lett. 638:83–89. 2017. View Article : Google Scholar : PubMed/NCBI

32 

Schefer V and Talan MI: Oxygen consumption in adult and Aged C57Bl/6J mice during acute treadmill exercise of different intensity. Exp Gerontol. 31:387–392. 1996. View Article : Google Scholar : PubMed/NCBI

33 

Kwon SJ, Park JS, Park SY, Song KS, Jung ST, Jung SB, Park IR, Choi WS and Kwon SO: Low-intensity treadmill exercise and/or bright light promote neurogenesis in adult rat brain. Neural Regen Res. 8:922–929. 2013.PubMed/NCBI

34 

Shimada H, Hamakawa M, Ishida A, Tamakoshi K, Nakashima H and Ishida K: Low-speed treadmill running exercise improves memory function after transient middle cerebral artery occlusion in rats. Behav Brain Res. 243:21–27. 2013. View Article : Google Scholar : PubMed/NCBI

35 

Alaei H, Moloudi R and Sarkaki AR: Effects of treadmill running on mid-term memory and swim speed in the rat with Morris water maze test. J Bodyw Mov Ther. 12:72–75. 2008. View Article : Google Scholar : PubMed/NCBI

36 

Sim YJ: Treadmill exercise alleviates impairment of spatial learning ability through enhancing cell proliferation in the streptozotocin-induced Alzheimer's disease rats. J Exerc Rehabil. 10:81–88. 2014. View Article : Google Scholar : PubMed/NCBI

37 

Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, Bennett ML, Münch AE, Chung WS, Peterson TC, et al: Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 541:481–487. 2017. View Article : Google Scholar : PubMed/NCBI

38 

Kim M, Shin MS, Lee JM, Cho HS, Kim CJ, Kim YJ, Choi HR and Jeon JW: Inhibitory effects of isoquinoline alkaloid berberine on ischemia-induced apoptosis via activation of phosphoinositide 3-kinase/protein kinase B signaling pathway. Int Neurourol J. 18:115–125. 2014. View Article : Google Scholar : PubMed/NCBI

39 

Bruce AJ, Boling W, Kindy MS, Peschon J, Kraemer PJ, Carpenter MK, Holtsberg FW and Mattson MP: Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors. Nat Med. 2:788–794. 1996. View Article : Google Scholar : PubMed/NCBI

40 

Vilhardt F: Microglia: Phagocyte and glia cell. Int J Biochem Cell Biol. 37:17–21. 2005. View Article : Google Scholar : PubMed/NCBI

41 

Cho HS, Kim TW, Ji ES, Park HS, Shin MS and Baek SS: Treadmill exercise ameliorates motor dysfunction through inhibition of Purkinje cell loss in cerebellum of valproic acid-induced autistic rats. J Exerc Rehabil. 12:293–298. 2016. View Article : Google Scholar : PubMed/NCBI

42 

Lee JM, Shin MS, Ji ES, Kim TW, Cho HS, Kim CJ, Jang MS, Kim TW, Kim BK and Kim DH: Treadmill exercise improves motor coordination through ameliorating Purkinje cell loss in amyloid beta23-35-induced Alzheimer's disease rats. J Exerc Rehabil. 10:258–264. 2014. View Article : Google Scholar : PubMed/NCBI

43 

Seo TB, Kim TW, Shin MS, Ji ES, Cho HS, Lee JM, Kim TW and Kim CJ: Aerobic exercise alleviates ischemia-induced memory impairment by enhancing cell proliferation and suppressing neuronal apoptosis in hippocampus. Int Neurourol J. 18:187–197. 2014. View Article : Google Scholar : PubMed/NCBI

44 

Marques-Aleixo I, Santos-Alves E, Balça MM, Rizo-Roca D, Moreira PI, Oliveira PJ, Magalhães J and Ascensão A: Physical exercise improves brain cortex and cerebellum mitochondrial bioenergetics and alters apoptotic, dynamic and auto(mito)phagy markers. Neuroscience. 301:480–495. 2015. View Article : Google Scholar : PubMed/NCBI

45 

Kim JE, Shin MS, Seo TB, Ji ES, Baek SS, Lee SJ, Park JK and Kim CJ: Treadmill exercise ameliorates motor disturbance through inhibition of apoptosis in the cerebellum of valproic acid-induced autistic rat pups. Mol Med Rep. 8:327–334. 2013. View Article : Google Scholar : PubMed/NCBI

46 

Kántor O, Schmitz C, Feiser J, Brasnjevic I, Korr H, Busto R, Ginsberg MD and Schmidt-Kastner R: Moderate loss of cerebellar Purkinje cells after chronic bilateral common carotid artery occlusion in rats. Acta Neuropathol. 113:549–558. 2007. View Article : Google Scholar : PubMed/NCBI

47 

Meng Y, Li WZ, Shi YW, Zhou BF, Ma R and Li WP: Danshensu protects against ischemia/reperfusion injury and inhibits the apoptosis of H9c2 cells by reducing the calcium overload through the p-JNK-NF-κB-TRPC6 pathway. Int J Mol Med. 37:258–266. 2016. View Article : Google Scholar : PubMed/NCBI

48 

Barski JJ, Hartmann J, Rose CR, Hoebeek F, Mörl K, Noll-Hussong M, De Zeeuw CI, Konnerth A and Meyer M: Calbindin in cerebellar Purkinje cells is a critical determinant of the precision of motor coordination. J Neurosci. 23:3469–3477. 2003. View Article : Google Scholar : PubMed/NCBI

49 

Gandhi CC, Kelly RM, Wiley RG and Walsh TJ: Impaired acquisition of a Morris water maze task following selective destruction of cerebellar purkinje cells with OX7-saporin. Behav Brain Res. 109:37–47. 2000. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

June 2018
Volume 17 Issue 6

Print ISSN: 1791-2997
Online ISSN:1791-3004

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Lee, J., Kim, C., Park, J., Song, M.K., & Kim, Y. (2018). Effect of treadmill exercise on spatial navigation impairment associated with cerebellar Purkinje cell loss following chronic cerebral hypoperfusion. Molecular Medicine Reports, 17, 8121-8128. https://doi.org/10.3892/mmr.2018.8893
MLA
Lee, J., Kim, C., Park, J., Song, M. K., Kim, Y."Effect of treadmill exercise on spatial navigation impairment associated with cerebellar Purkinje cell loss following chronic cerebral hypoperfusion". Molecular Medicine Reports 17.6 (2018): 8121-8128.
Chicago
Lee, J., Kim, C., Park, J., Song, M. K., Kim, Y."Effect of treadmill exercise on spatial navigation impairment associated with cerebellar Purkinje cell loss following chronic cerebral hypoperfusion". Molecular Medicine Reports 17, no. 6 (2018): 8121-8128. https://doi.org/10.3892/mmr.2018.8893