The benefits of high-intensity physical exercise before and after Parkinson’s disease induction in ratsAbstract
High-intensity physical activity is a non-pharmacological intervention that has been tested as a treatment for Parkinson’s disease (PD). The objective of the study was to investigate the benefits of high-intensity physical exercise on the number of neurons and astrocytes in a a rat model of Parkinson’s disease submitted to training before and after the inducing injury. Seventy Wistar rats were used, distributed as follows: nine rats trained before PD induction (DP-Exa), nine trained after PD induction (DP-Exd), 10 trained before and after PD induction (DP-Exad), and nine sedentary rats (DP-Sed). There were also the same groups but with the rats exposed to the sham surgery (control). High-intensity physical exercise on a vertical ladder was performed before and/or after PD induction for 5 days/week, 30-45 min a day, for 4 weeks. PD was induced with an electrolytic lesion (AP -4.9, ML 1.7, and DV 8.1). At the end of the experiment, the brain was removed for Nissl staining and immunohistochemistry of glial fibrillary acidid protein (GFAP) in the substantia nigra and striatum. The DP-Exa, Sham-Exa, DP-Exad, and Sham-Exad groups showed a greater number of neurons and higher expression of GFAP in the substantia nigra and stiatum compared with the the DP-Exd, Sham-Exd, DP-Sed, and Sham-Sed groups. Thus, rats that performed high-intensity training before or before and after PD induction had higher densities of neurons and astrocytes.
Keywords:
parkinson disease; exercise; neuroprotection
Resumo
A prática de atividade física de alta intensidade é uma intervenção não farmacológica que vem sendo testada no tratamento da Doença de Parkinson (DP). O objetivo do estudo é investigar os benefícios do exercício físico de alta intensidade sobre a densidade neuronal e expressão de astrócitos no cérebro de ratos com DP que praticaram exercícios antes e após a indução da doença. Foram utilizados 70 ratos Wistar, assim distribuídos: 09 animais treinados antes da indução da DP (DP-Exa), 09 animais treinados após a indução da DP (DP-Exd); 10 animais treinados antes e após a indução da DP (DP-Exad) e 09 animais sedentários (DP-Sed). Os mesmos grupos foram distribuídos para o grupo sem DP (Sham). O exercício físico de alta intensidade foi realizado na escada vertical antes e/ou após a indução da DP. Foi realizado 5 dias/semana, 30 a 45 minutos, durante 4 semanas. A indução da DP foi realizada utilizando o modelo de lesão eletrolítica nas coordenadas: AP igual a -4,9, ML igual a 1,7 e DV igual a 8,1. Ao final do experimento, o cérebro foi retirado para histoquímica, por coloração de Nissl, e imuno-histoquímica para expressão da Proteína Ácida Fibrilar Glial (GFAP) dos astrócitos da substância negra e do corpo estriado. Dados de contagens de neurônios no estriado, substância negra e GFAP nos animais dos grupos DP-Exa, Sham-Exa, DP-Exad e Sham-Exad mostraram maior número de neurônios e maior expressão de GFAP, quando comparados ao DP grupos. -Exd, Sham-Exd, DP-Sed e Sham-Sed. Animais que realizaram treinamento de alta intensidade antes, antes e após a indução da DP apresentaram maiores densidades de neurônios e astrócitos.
Palavras-chave:
doença de parkinson; exercício; neuroproteção
1. Introduction
Parkinson's Disease (PD) is a progressive neurodegenerative disease defined by the presence of debilitating motor symptoms, including bradykinesia, tremors, and muscle rigidity, as well as non-motor symptoms, namely intestinal dysfunction, depression, cognitive decline, sleep disturbances (Lees et al., 2009; Freire et al., 2015). Its etiology is idiopathic, but it is believed to arise from environmental and genetic factors, with changes in the intestinal microbiota and aging, which is the main risk factor, due to the acceleration of the loss of dopaminergic neurons over time (Souza et al., 2011; Sampson et al., 2016). According to data from the World Health Organization (WHO), PD affects more than 1% of the population over 65 years of age. Considering population aging and the impact of the disease on the economy and society, it is extremely important to develop less expensive and more effective treatments (Santos, 2015). Thus, researchers have developed methods and strategies that stimulate neuronal plasticity (Guimarães et al., 2023), including physical training, as a proposed therapeutic intervention (Pondé et al., 2019).
Many researchers have used animal models of PD to assess the musculoskeletal adaptations that accompany physical exercise, and to understand the physiological, biochemical, and morphofunctional changes in the disease (Damiani et al., 2020). The benefit of regular and systematic physical activity has been associated with neuroprotective and activating effects of the nigrostriatal dopaminergic system (Yang et al., 2015; Melo et al., 2019). The practice of resistance physical activity is a non-pharmacological intervention that has been evaluated as a treatment for PD (Schenkman, et al., 2018). Physical exercise is recognized as a preventive and therapeutic alternative for various diseases (Ahlskog, 2011; Petzinger et al., 2013; Mendes et al., 2024). Consistently, there is evidence that regular systematic physical activity has a neuroprotective role in PD (Yang et al., 2015; Melo et al., 2019). Studies with light- and medium-intensity physical exercise have been proven its ability to improve the musculoskeletal system of these individuals (Rubert, et al., 2007). However, high-intensity exercise has not yet been tested in animal models of PD (Yang, et al., 2015).
There have been very few studies on how high-intensity exercise could help recover motor performance and increase the density of neurons and astrocytes in the brain of rat models of PD. Astrocytes provide neuroprotection for nervous tissue by transporting various molecules and reducing excitotoxicity. Analysis of the number of astrocytes in nervous tissue is important to identify neuroprotection induced by progressive resistance physical exercise as a therapeutic intervention for PD (Sofroniew and Vinters, 2010). Thus, we evaluated the effect of physical training before, before and after, or after an electrolytic injury that mimics PD in rats, on the motor function and the number of neurons and astrocytes in the substantia nigra and striatum. These results that may guide the implementation of preventive and therapeutic strategies based on physical exercise.
2. Materials and Methods
2.1. Experimental animals
This study followed international and national standards for experimentation with laboratory animals. It was approved by the Ethics Committee on the Use of Animals of the Federal University of São João Del Rei (UFSJ), according to protocol number 9049140321.
Seventy 40-day-old male Wistar rats (Rattus norvegicus var. albinus, 250-450 g) were used. They were housed in polypropylene cages at 21-22 °C, 60-70% relative humidity, a 12-h photoperiod, and free access to food and water. The rats were divided into two experimental groups: the PD group underwent an electrolytic lesion of the substantia nigra (Gomes and Del Bel, 2003; see section 2.3 for details) and the sham group underwent the surgical procedure but not the electrolytic lesion. They were weighed at the beginning of the 80-day experiment, after the surgery, and at the end of the experiment.
There were 37 rats that underwent electrolytic injury to induce PD. They were randomly assigned to the following subgroups: DP-Exa, nine rats underwent physical training before the electrolytic lesion; DP-Exd, nine rats underwent physical training after the electrolytic lesion; DP-Exad, 10 rats underwent physical training before and after the electrolytic lesion; and DP-Sed, nine sedentary animals (no physical training) that received the electrolytic lesion. In addition, 33 rats underwent the sham surgical procedure. They were distributed into the following subgroups: Sham-Exa, seven rats underwent physical training before the sham surgery; Sham-Exd, eight rats underwent physical training after undergoing the sham surgery; Sham-Exad, 10 rats underwent physical training before and after the sham surgery; and Sham-Sed, eight sedentary rats (no physical training) underwent the sham surgery. Figure 1 provides a representation of the experimental procedures.
2.2. Physical training
The groups that received physical training were adapted to the ladder used for physical training for 3 days prior to the start of training. They performed three attempts per day, without overload. The rat was positioned in the housing chamber for 60 s to familiarize itself with the environment. In the first attempt, the rat remained 35 cm from the chamber; this distance increased to 55 cm for the second attempt and 110 cm for the third attempt. The vertical ladder was modified from the study by Peixinho-Pena et al. (2012). It was 110 cm long, 18 cm wide, and had an 80° incline. The box at the top end of the stairs was 20 cm high, 20 cm wide, and and divided into 20-cm sectors. After the adaptation period, the rats that underwent the high-intensity training protocol were submitted to stair exercise for 4 weeks, 5 days a week, with an average duration of 30-45 min per session, with eight sessions of eight climbs. The first and second climbs had 50% of the rat’s body weight, the third and fourth climbs had 75% of the rat’s body weight, the fifth and sixth climbs had 90% of the rat’s body weight, and the seventh and eighth climbs had 100% of the rat’s body weight (Hornberger Junior and Farrar, 2004; Peixinho-Pena et al., 2012). The weight used was fixed on the proximal portion of the rat’s tail, 3 cm from its caudal root. It was a cylindrical shape (16 cm in length) secured with a wool line wrapped by an adhesive rubber tape to protect the rat’s skin (Hornberger Junior and Farrar, 2004, 2004; Peixinho-Pena et al., 2012; Cassilhas et al., 2013). The maximum heart rate (HRmax) and the oxygen saturation (SatO2) were monitored with a pulse oximeter (Contec®) so that the rat reached 80-95% of its HRmax while exercising. The interval between each set was 60 s; during this time, the rat rested in the housing chamber.
2.3. PD induction surgery
PD was induced using an electrolytic lesion, as described previously (Gomes and Del Bel, 2003). The rat received an intraperitoneal injection of ketamine (75 mg/kg body weight) and xylazine (10 mg/kg body weight) (Sigma-Aldrich). After being anesthetized, the rat’s head was positioned on the stereotaxic table. The region where the surgical procedure was performed was cleaned with iodized alcohol. The periosteum from lambda to bregma, followed by the application of an electrode for electrolytic stimulation. The coordinates for electrode application were AP -4.9, ML 1.7, and DV 8.1 (Blanco Lezcano et al., 2010). The electrode delivered a current load of 1 mA for 10 s to injure the substantia nigra; it remained in place after the injury for approximately 3 min. Finally, the wound was sutured with a surgical thread.
2.4. Motor performance
Functional tests (the parallel bars test, the open field test, and the false step test) were performed before surgery, after surgery, and before sacrifice to assess motor performance. The false step test used a 100 × 50 cm grid plate, with a grid interval of 3 × 3 cm (9 cm2). The test lasted 3 min. An error occurred when the rat’s paw passed through the grid (Ding et al., 2002, 2004; Lim et al., 2008). The parallel bars test used two wooden platforms joined by parallel metal bars (115 cm) without aversive stimulus (electric shock) at the ends of the bars. The test lasted for 5 min. An error occurred when the rat placed both paws on the same bar or when its paw passed between the two bars or outside (Ding et al., 2002, 2004). In the open field test, the rat was positioned in the center of a box with the flood divided into quadrants for 5 min to evaluate its exploratory behavior: the number of quadrants visited (when the rat placed three of its limbs in the quadrant), the number of times it climbed the walls, and the number of times it raised its body and touched the wall of the box (Ingelsrud, 2016).
2.5. Histochemistry
After the exercise program, each rat was euthanized and its brain removed. The brain was fixed in 10% buffered formalin for 24 h and then in 70% alcohol. Then, it was embedded in paraffin and 1-mm coronal sections were cut (Junqueira and Carneiro, 2017). The sections were stained using the Nissl method to count the number of neurons in the substantia nigra and the striatum of the right and left cerebral hemispheres. Images using a microscope with a 20× objective lens (Motic 580) and an attached camera.
The Image-Pro Plus software (version 4.5, Windows 98) was used to analyze the images. For quantification of neurons, the largest cells stained with cresyl violet dye (Nissl bodies) in the cytoplasm of neurons were considered (Scorza et al., 2005).
2.6. Glial fibrillary acidic protein (GFAP) immunohistochemistry
Slides with sections were washed in phosphate-buffered saline (PBS) and incubated with polyclonal anti-GFAP antibody (Dako Z-334). Then, slides were washed in PBS and incubated with diaminobenzidine (Sigma D-9015) 0.03% plus 0.03% hydrogen peroxide for 5-8 min (a microscope was used to control the intensity of the chromogenic reaction). Afterwards, the slides were washed in running water, dehydrated in alcohol, and mounted with a coverslip. To quantify astrocytes, the cells expressing GFAP were counted (i.e., the cells whose cytoplasm was brown based on the immunohistochemical reaction).
2.7. Data analysis
The results are expressed as the mean ± standard error of the mean. The data were analyzed with one-way analysis of variance (ANOVA) followed by Tukey’s post hoc test for pairwise comparisons, with a significance level of 5%. GraphPad Prism 10.3 was used for the data analysis.
3. Results
3.1. Electrolytic injury to the Substantia Negra
Based on Nissl staining, the electrolytic lesion damaged the substantia nigra of the rats in the DP-Exa, DP-Exd, DP-Exad, and DP-Sed groups (Figure 2).
A photomicrograph of the substantia nigra from a rat with Parkinson’s disease (4× magnification).
3.2. Body weight
When comparing the initial and final weights, the DP and Sham groups gained weight (Table 1). Specifically, the DP-Exad and Sham-Exad groups showed the greatest body weight gain (p < 0.0001).
3.3. Functional performance
In the parallel bars test, the DP-Exad group presented fewer errors and better functional performance. The DP-Exa group showed no significant decrease in the number of errors after training. The Sham-Exa, Sham-Exd, and Sham-Exad groups also showed fewer errors (Table 2).
In the false step test, there was significant worsening of functional performance in the right and left forelegs in almost all groups (p < 0.05). There was a significant difference in the number of errors after the electrolytic lesion compared with before the injury in the front right paw of the DP-Exa, DP-Exd, and DP-Sed groups, and in the front left paw in the DP-Exa and DP-Exd groups (Table 3).
For the open field test, there were significant differences in the number of wall climbs and the number of quadrants visited. There were significant differences for the DP-Exa/Sham-Exa and DP-Exad/Sham-Exad compared with the DP-Exd and Sham-Exd groups (p < 0.0001). Before the electrolytic lesion or sham surgery, there were no significant difference between the PD and sham groups (Figure 3 and Table 4). After the electrolytic lesion or sham surgery, the DP-Exa/Sham-Exa and DP-Exad/Sham-Exad groups had a higher mean number of wall climbs and quadrants visited compared with the DP-Exd/Sham-Exd and DP-Sed/Sham-Sed groups (p < 0.0001). Moreover, there were significant differences between the PD and sham groups (Table 5).
The mean number of (A) wall climbs and (B) quadrants visited in the open field test before surgery. DP-Exa – physical training before the electrolytic lesion; DP-Exd – physical training after the electrolytic lesion; DP-Exad – physical training before and after the electrolytic lesion; DP-Sed – no physical training before or after the electrolytic lesion; Sham-Exa – physical training before the sham surgery; Sham-Exd – physical training after the sham surgery; Sham-Exad – physical training before and after the sham surgery; Sham-Sed – no physical training before or after the sham surgery. The data were analyzed with one-way analysis of variance followed by Tukey’s post hoc test (p < 0.05). **<0,0001.
The means number of wall climbs and quadrants visited in the open field test after training and/or before surgery.
3.4. Quantification of neurons in the substantia nigra
In general, the trained groups showed more neurons than the sedentary groups. In the left substantia nigra, there were significant differences in the mean number of neurons between the DP-Exa, Sham-Exa, DP-Exad, and Sham-Exad groups and the DP-Exd, Sham-Exd, DP-Sed, and Sham-Sed groups. The groups that underwent physical training exercised before or before and after surgery showed the highest mean number of neurons (Figure 4 and Table 6).
The mean number of neurons in the left and right substantia nigra. Photomicrographs (4× and 20× magnification) of the substantia nigra of (A) an Exa rat, (B) an Exd rat, (C) an Exad rat, and (D) a Sed rat. The mean number of neurons in the (E) left and (F) right substantia nigra. DP-Exa – physical training before the electrolytic lesion; DP-Exd – physical training after the electrolytic lesion; DP-Exad – physical training before and after the electrolytic lesion; DP-Sed – no physical training before or after the electrolytic lesion; Sham-Exa – physical training before the sham surgery; Sham-Exd – physical training after the sham surgery; Sham-Exad – physical training before and after the sham surgery; Sham-Sed – no physical training before or after the sham surgery. The data were analyzed with one-way analysis of variance followed by Tukey’s post hoc test (p < 0.05).
3.5. Quantification of the number of neurons in the striatum
In general, the trained groups showed more neurons than the sedentary groups. In the left striatum, there were significant differences in the number of neurons between the DP-Exa, Sham-Exa, DP-Exad, and Sham-Exad groups compared with the DP-Exd, Sham-Exd, DP-Sed, and Sham-Sed groups. The groups that underwent physical training before or before and after surgery showed a higher mean number of neurons (Figure 5 and Table 7).
The mean number of neurons in the (A) left and (B) right striatum. DP-Exa – physical training before the electrolytic lesion; DP-Exd – physical training after the electrolytic lesion; DP-Exad – physical training before and after the electrolytic lesion; DP-Sed – no physical training before or after the electrolytic lesion; Sham-Exa – physical training before the sham surgery; Sham-Exd – physical training after the sham surgery; Sham-Exad – physical training before and after the sham surgery; Sham-Sed – no physical training before or after the sham surgery. The data were analyzed with one-way analysis of variance followed by Tukey’s post hoc test (p < 0.05).
3.6. Quantification of GFAP expression
In the left substantia nigra, there was a higher mean number of astrocytes in the DP-Exa, Sham-Exa, and Sham-Exd groups. In the right substantia nigra, there was a higher mean number of astrocytes in the DP-Exa, Sham-Exa, DP-Exad, and Sham-Exad groups (Figure 6 and Table 8).
The mean number of astrocytes that express glial fibrillary acidic protein (GFAP) in the substantia nigra. Photomicrographs (100× magnification) of the (A) left and (B) right substantia nigra showing cells that express GFAP. The arrows indicate astrocytes. The mean number of astrocytes that express GFAP in the (C) left and (D) right substantia nigra. DP-Exa – physical training before the electrolytic lesion; DP-Exd – physical training after the electrolytic lesion; DP-Exad – physical training before and after the electrolytic lesion; DP-Sed – no physical training before or after the electrolytic lesion; Sham-Exa – physical training before the sham surgery; Sham-Exd – physical training after the sham surgery; Sham-Exad – physical training before and after the sham surgery; Sham-Sed – no physical training before or after the sham surgery. The data were analyzed with one-way analysis of variance followed by Tukey’s post hoc test (p < 0.05). **<0,0001.
The mean number of astrocytes (expressing glial fibrillary acidic protein [GFAP]) in the left and right substantia nigra.
4. Discussion
Rats submitted to high-intensity training presented better functional test results and a higher number of neurons and astrocytes compared with sedentary rats. High-intensity training before or before and after electrolytic injury exerted a greater neuroprotective effect than high-intensity training only after electrolytic surgery.
In the open field test, there were significant differences in the number of wall climbs and quandrants visits in the groups that underwent training before or before and after electrolytic injury compared with the rats that only underwent training after electrolytic injury and the sedentary group. These data corroborate the findings reported by Barbosa and Lima (2016), who reported a higher number of displacements between the quadrants in the trained group compared with the control group.
The left and right substantia nigra and striatum of the trained rats showed a greater number of neurons compared with the sedentary rats. That rats that were trained before or before and after the surgery had more neurons than the rats that were trained only after the surgery. These findings suggest that high-intensity physical exercise before an injury to the nervous system provides neuroprotection. Consistently, physical exercise reduces toxicity and protects nervous tissue: Damázio et al. (2014) evidenced greater neuronal density in the animals that exercised before or before and after the induction of cerebral ischemia. Moreover, astrocytes take up PD-causing molecules and decrease dopaminergic toxicity (Chen et al., 2009). Fischer et al. (2004) investigated the effect of neurorestoration through treadmill exercise in C57BL/6J mice. Physical exercise promoted behavioral recovery in the injured brain, modulating the expression of genes and proteins related to the basal ganglia. According to Nascimento et al. (2017), voluntary physical exercise (EFV) exerted positive effects on hippocampal function in C57BL/6 mice. EFV could be applied in humans based on its positive neurological effects in animal models. According to Ke et al. (2011), EFV is an effective method to regulate hippocampal brain-derived neurotrophic factor (BDNF) in rats with ischemia during motor recovery. By contrast, the group submitted to forced exercise had low levels of brain BDNF and lower motor recovery; moreover, forced exercise induces a high level of stress in the animals.
Astrocytes play an important role in repairing and maintaining nervous tissue against damage (Sofroniew and Vinters, 2010). In the present study, there was higher GFAP expression in the left substantia nigra in the rats trained before or before and after the electrolytic injury. In the right substantia nigra, only the rats trained before the electrolytic injury showed higher GFAP expression. Dutra et al. (2012) reported an increase in GFAP expression in rats with PD induced by injection of 6-OHDA and then underwent training on the treadmill. In addition, the animals presented motor improvement. Some authors have demonstrated that physical exercise on a treadmill promotes a neuroprotective effect on nervous tissue as well as an increase in the number of astrocytes in the cortex and the striatum (Li et al., 2005; Yoon et al., 2007; Tajiri et al., 2010; Lau et al., 2011; Damázio et al., 2014). Vasconcelos et al. (2021) examined high-intensity physical training (in the strength gain modality) in rats with cerebral ischemia induced by bilateral common carotid artery occlusion. This procedure promoted significant damage to the rat brain. High-intensity exercise ameliorated this damage by modulating cerebral blood flow.
5. Conclusion
High-intensity physical exercise before and after an electrolytic injury that induces PD in rats improved motor performance and the number of neurons and astrocytes compared with the sedentary group.
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Publication Dates
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Publication in this collection
14 Oct 2024 -
Date of issue
2024
History
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Received
19 Jan 2024 -
Accepted
15 Aug 2024
