15 January 2020
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In addition to motor symptoms, Parkinson's disease (PD) presents high prevalence of painful symptoms responsible for worsening quality of life of PD patients. Physical exercise can improve such painful symptoms. This study evaluated the effects of exercise on nociceptive threshold using an unilateral rat model of PD, as well as the role played by cannabinoid and opioid receptors in areas responsible for pain pathways.
For PD induction, Wistar rats were injected with 6-OHDA. 15 days after, rats either remained sedentary or were forced to exercise three times a week for 40 min. Motor and nociceptive behaviors were evaluated through cylinder and mechanical hyperalgesia tests, respectively. The animals were euthanized for analysis of cannabinoid receptor type 1 (CB1) and type 2 (CB2), and μ-opioid receptor (MOR) in the anterior cingulate cortex (ACC), periaqueductal gray matter (PAG), and thalamus areas by immunohistochemistry (IHC) and Western blotting.
Our data revealed a decrease in the nociceptive threshold in both forepaws after surgery; in contrast, there was improvement in painful symptoms after the exercise protocol. For cannabinoid system there were an increase in CB2 expression in the ACC and PAG, and in CB1 levels in the PAG. And for opioid system there was an increase of MOR expression in the thalamus.
Thus, modulation of those receptors by physical exercise can be an important non-pharmacological intervention to reduce painful symptoms in a rat model of PD, contributing to knowledge and promotion of better treatment aimed at improving the quality of life of PD patients.
In addition to motor symptoms, painful symptoms occur in approximately 85% of patients with Parkinson’s disease (PD) (Cury et al., 2016). In most PD cases, pain appears before motor and cognitive symptoms and intensifies with disease progresses (Buhmann et al., 2017). Pain symptoms reduce the quality of life of PD patients, as it is directly associated with emotional and cognitive impairments, such as depression and anxiety (Allen et al., 2015, Buhmann et al., 2017). Although pain is one of the most disturbing and common symptoms experienced by individuals with PD, it still receives little attention in clinical practice, lacking in acknowledgement, diagnosis, and treatment (Broen et al., 2012).
The origin of pain in PD remains poorly understood (Skogar and Lokk, 2016), and studies addressing changes in brain circuits changes or firing patterns in pain processing circuits are scarce (Gee et al., 2016). Few previous studies have described a correlation between pain threshold and activation of the anterior cingulate cortex (ACC) (Fillinger et al., 2017). On the other hand, deep brain stimulation in 6-OHDA animal models revealed an increase analgesia through decrease in ACC excitatory projections to the periaqueductal gray matter (PAG) (Gee et al., 2016). In addition, desynchronized thalamo-cortical oscillations have been strongly associated with the development of chronic pain (Walton et al., 2010).
PD is classically treated with levodopa, since it is able to decrease not only motor symptoms but also painful symptoms in some cases (Brefel-Courbon et al., 2013). However, chronic administration of levodopa can cause serious side effects, such as severe and disabling dyskinesias, which restricts the use of levodopa as a continuous treatment (Ahlskog and Muenter, 2001). Thus, it is relevant to develop non-pharmacological interventions, such as physical exercise, that contribute to reducing excessive consumption of analgesics and improvement of quality of life of PD patients. Recently, many clinical studies conducted with PD patients (Allen et al., 2015) and neuropathic pain animal models (Stagg et al., 2011) have indicated the beneficial effects of physical exercise in PD, focusing on painful symptoms; however, there is still a gap in the understanding of the cellular and molecular mechanisms that may be involved in PD chronic pain improvement after different exercise protocols.
Although there are not studies with PD models and exercise protocols, a study conducted with healthy rats showed that physical exercise on a treadmill is able to promote antinociception in mechanical and thermal tests, possibly due to the activation of the endocannabinoid system, since the effects were reversed after administration of the cannabinoid receptor antagonists (CB1 and CB2). In addition to improving behavior, there was an increase in CB1 receptors, especially in the PAG (Galdino et al., 2014). In a neuropathic pain model, in addition to the involvement of cannabinoid receptors, opioid receptors revealed an important role in the nociceptive threshold increase after treadmill exercise protocol, as the administration of an antagonist, naloxone, can reverse beneficial effects of exercise (Stagg et al., 2011). In addition, another study conducted with healthy rats reported that short-term exercise (acute effect) was capable of increasing expression of the μ-opioid receptor (MOR) on the hippocampus (de Oliveira et al., 2010).
So, the present study aims to understand the effect of treadmill exercise on nociceptive pathways in rats submitted to unilateral PD model induced by 6-hydroxydopamine (6-OHDA). For that, we analyzed the expression of cannabinoid and opioid receptors in areas of the CNS, which are directly involved in the nociceptive process, such as the periaqueductal gray matter, anterior cingulate cortex, and thalamus. In addition, we analyzed the motor and nociceptive behavior by cylinder and mechanical hyperalgesia tests. Fig. 1
PD model induction validation
To confirm model induction by 6-OHDA, we performed tyrosine hydroxylase (TH) analysis for dopaminergic system, and behavioral tests. After PD model induction, we observed a optical density decrease of TH in the caudate-putamen (CPu) and in the number of positive dopaminergic cells in the substantia nigra pars compacta (SNc) in the experimental hemisphere in both groups injected with 6-OHDA (6-OHDA + EX and 6-OHDA + SED) compared with the groups injected with saline (SAL + EX and SAL + SED),
Overall, the cylinder test for asymmetric forelimb use and analysis of TH expression confirmed the induction of the unilateral PD rat model. TH data in the 6-OHDA groups, 6-OHDA + SED and 6-OHDA + EX, revealed a neurodegeneration of dopaminergic cells from SNc and a consequent decrease in the optical density of the TH in the CPu. In addition, we measured the body weight of the animals and verified that it remained similar among the groups throughout the entire protocol. Therefore, it may be
Strength and limitations
All animal models have limitations, since in most of the animal models they cannot mimic the exact processes that occur in patients. 6-OHDA model for PD is widely used by researches as PD model, including studies which focused PD and pain pathways (Domenici et al., 2019), in despite of transgenic model of PD, which were introduced in researchers recently and for that there are few studies reported (Valek et al., 2019). In addition, pain in PD is a new field on preclinical studies and this is
The experiments were carried out in accordance with the CONCEA guidelines (CONCEA, Brazil), a constituent body of the Ministry of Science, Technology, and Innovation (MCTI, Brazil). All protocols were approved by the Animal Research Ethics Committee (CEUA) of the Institute of Biomedical Sciences of the University Sao Paulo (protocol n° 4860310118). All animals were handled as per the principles and guidelines for use of laboratory animals involving pain and nociception (Zimmermann, 1983). The
This study was supported by The São Paulo Research Foundation (FAPESP, Brazil). KHB and Chacur, M were the recipient of a fellowship from FAPESP (2017/26821-1 and 2017/05218-5, respectively).
KHB, MC, and CCR designed the experiments; KHB, AFFF, CCR, and MC collected the data; KHB and MC analyzed the data; KHB, MC, CCR, and AFFF wrote the paper; All of the authors discussed the data, along with editing and commenting on the manuscript, having then approved its final version.
Financial disclosures of all authors
KHB – Master’s scholarship from The São Paulo Research Foundation (FAPESP), Brazil – Grant number: 2017/26821-1.
CCR – Post-doctoral scholarship from General Electric Healthcare (GE healthcare) – Fundação Faculdade de Medicina (FFM).
AFFF- Master’s scholarship from Coordination of Improvement of Higher-Level Personnel (CAPES).
LRB – supported by The São Paulo Research Foundation (FAPESP), Brazil – Grant Number: 2012/50329-6 and National Council for Scientific and Technological Development (CNPq),
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Parkin protects against neurotoxicity in the 6-hydroxydopamine rat model for Parkinson's disease
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Gabapentin decreases microglial cells and reverses bilateral hyperalgesia and allodynia in rats with chronic myositis
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BDNF receptor blockade hinders the beneficial effects of exercise in a rat model of Parkinson's disease
A method to perform direct transcutaneous intrathecal injection in rats
J. Pharmacol. Toxicol. Methods
Neuroimaging of the periaqueductal gray: state of the field
Effects of subthalamic deep brain stimulation with duloxetine on mechanical and thermal thresholds in 6OHDA lesioned rats
Endogenous protection against the 6-OHDA model of Parkinson's disease in the Amazonian rodent Proechimys
Neuroprotective effects of swimming training in a mouse model of Parkinson's disease induced by 6-hydroxydopamine
Subthalamic deep brain stimulation alters neuronal firing in canonical pain nuclei in a 6-hydroxydopamine lesioned rat model of Parkinson's disease
The endocannabinoid system mediates aerobic exercise-induced antinociception in rats
Comparison of bilaterally 6-OHDA- and MPTP-lesioned rats as models of the early phase of Parkinson's disease: histological, neurochemical, motor and memory alterations
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Parkinson's disease and pain: Modulation of nociceptive circuitry in a rat model of nigrostriatal lesion
Modeling Parkinson's disease in rats: an evaluation of 6-OHDA lesions of the nigrostriatal pathway
Acute and chronic exercise modulates the expression of MOR opioid receptors in the hippocampal formation of rats
Brain Res. Bull.
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A partial lesion model of Parkinson's disease in mice–characterization of a 6-OHDA-induced medial forebrain bundle lesion
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Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature
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The rationale for exercise in the management of pain in Parkinson's disease
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New approaches to treatments for sleep, pain and autonomic failure in Parkinson's disease - Pharmacological therapies
Non-motor symptoms (NMSs) are highly prevalent throughout the course of Parkinson's disease (PD). Pain, autonomic dysfunction and sleep disturbances remain at the forefront of the most common NMSs; their treatment is challenging and their effect on the quality of life of both patients and caregivers detrimental. Yet, the landscape of clinical trials in PD is still dominated by therapeutic strategies seeking to ameliorate motor symptoms; subsequently, effective strategies to successfully treat NMSs remain a huge unmet need. Wider awareness among industry and researchers is thus essential to give rise to development and delivery of high-quality, large-scale clinical trials in enriched populations of patients with PD-related pain, autonomic dysfunction and sleep.
In this review, we discuss recent developments in the field of pharmacological treatment strategies designed or re-purposed to target three key NMSs: pain, autonomic dysfunction and sleep disturbances. We focus on emerging evidence from recent clinical trials and outline some exciting and intriguing findings that call for further investigations.
This article is part of the Special Issue on ‘New therapeutic approaches to Parkinson’s disease'.
The effects of treadmill exercise in animal models of Parkinson's disease: A systematic review
2021, Neuroscience and Biobehavioral Reviews
Parkinson’s disease (PD) is a progressive disabling brain disorder. Physical exercise has been shown to alleviate the symptoms of PD and, consequently, improve patient quality of life. Exercise mechanisms involved in beneficial effects on PD have been widely investigated. This study aims to systematically review the literature on the use of treadmill exercise in PD animal models. The study was conducted according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA). Searches were conducted in MEDLINE, EMBASE, and ISI databases. In total, 78 studies were included. The dopaminergic system, behavior, neuroplasticity, neuroinflammation, mitochondria, and musculoskeletal systems were some of the outcomes evaluated by the selected studies. Based on the systematic review center for laboratory animal experimentation (SYRCLE) RoB tool, the methodologies revealed a high risk of bias and lack of information about study design, which needs attention for data reproducibility. This review can guide future studies that aim to fill existing gaps regarding the effects of treadmill exercise in PD animal models.
Exercise protects synaptic density in a rat model of Parkinson's disease
2021, Experimental Neurology
Parkinson's disease (PD) is characterized by Lewy body and neurite pathology associated with dopamine terminal dysfunction. Clinically, it is associated with motor slowing, rigidity, and tremor. Postural instability and pain are also features. Physical exercise benefits PD patients - possibly by promoting neuroplasticity including synaptic regeneration.
In a parkinsonian rat model, we test the hypotheses that exercise: (a) increases synaptic density and reduces neuroinflammation and (b) lowers the nociceptive threshold by increasing μ-opioid receptor expression.
Brain autoradiography was performed on rats unilaterally injected with either 6-hydroxydopamine (6-OHDA) or saline and subjected to treadmill exercise over 5weeks. [3H]UCB-J was used to measure synaptic vesicle glycoprotein 2A (SV2A) density. Dopamine D2/3 receptor and μ-opioid receptor availability were assessed with [3H]Raclopride and [3H]DAMGO, respectively, while neuroinflammation was detected with the 18kDA translocator protein (TSPO) marker [3H]PK11195. The nociceptive threshold was determined prior to and throughout the exercise protocol.
We confirmed a dopaminegic deficit with increased striatal [3H]Raclopride D2/3 receptor availability and reduced nigral tyrosine hydroxylase immunoreactivity in the ipsilateral hemisphere of all 6-OHDA-injected rats. Sedentary rats lesioned with 6-OHDA showed significant reduction of ipsilateral striatal and substantia nigra [3H]UCB-J binding while [3H]PK11195 showed increased ipsilateral striatal neuroinflammation. Lesioned rats who exercised had higher levels of ipsilateral striatal [3H]UCB-J binding and lower levels of neuroinflammation compared to sedentary lesioned rats. Striatal 6-OHDA injections reduced thalamic μ-opioid receptor availability but subsequent exercise restored binding. Exercise also raised thalamic and hippocampal SV2A synaptic density in 6-OHDA lesioned rats, accompanied by a rise in nociceptive threshold.
These data suggest that treadmill exercise protects nigral and striatal synaptic integrity in a rat lesion model of PD - possibly by promoting compensatory mechanisms. Exercise was also associated with reduced neuroinflammation post lesioning and altered opioid transmission resulting in an increased nociceptive threshold.
Physical exercise protects against mitochondria alterations in the 6-hidroxydopamine rat model of Parkinson's disease
2020, Behavioural Brain Research
Parkinson’s disease (PD) is typicaly caractherized by loss of dopaminergic neurons, as well as the presence of mitochondrial impairments. Although physical exercise is known to promote many beneficial effects in healthy subjects, such as enhancing mitocondrial biogenesis and function, it is not clear if these effects are evident after exercise in individuals with PD. The aim of this study was to investigate the effects of two different protocol durations on motor behavior (aphomorphine and gait tests), mitochondrial biogenesis signaling (PGC-1α, NRF-1 and TFAM), structure (oxidative phosphorylation system protein levels) and respiratory chain activity (complex I) in a unilateral PD rat model. For this, male Wistar rats were injected with 6-hydroxydopamine unilaterally into the striatum and submitted to an intermitent moderate treadmill exercise for one or four weeks. In the gait test, only stride width data revealed an improvement after one week of exercise. On the other hand, after 4 weeks of the exercise protocol all gait parameters analyzed and the aphomorphine test demonstrated a recovery. Analysis of protein revealed that one week of exercise was able to prevent PGC-1α and NRF-1 expression decrease in PD animals. In addition, after four weeks of physical exercise, besides PGC-1α and NRF-1, reduction in TFAM and complex I protein levels and increased complex I activity were also prevented in PD animals. Thus, our results suggest a neuroprotective and progressive effect of intermittent treadmill exercise, which could be related to its benefits on mitochondrial biogenesis signaling and respiratory chain modulation of the dopaminergic system in PD.
The Role of Cannabinoid Type 2 Receptors in Parkinson’s Disease
Inhibition of TRPM2 by AG490 Is Neuroprotective in a Parkinson’s Disease Animal Model
2022, Molecular Neurobiology
Attenuated baroreflex in a Parkinson's disease animal model coincides with impaired activation of non-C1 neurons
Autonomic Neuroscience, Volume 225, 2020, Article 102655
Orthostatic hypotension is one of the most common symptoms observed in Parkinson's disease (PD), a neurodegenerative disease caused by death of dopaminergic neurons in the substantia nigra pars compacta (SNc), and it is associated with denervation of the heart and impairment of the baroreflex. Here, we aimed to investigate if the impaired baroreflex was associated with lower activation of cardiovascular brainstem areas in a 6-hydroxydopamine (6-OHDA) animal model of PD. The PD model was generated with male Wistar rats by injection of 6-OHDA or vehicle into the striatum. After 20 or 60days, the femoral vein and artery were cannulated to assess cardiovascular parameters during injection of sodium nitroprusside (SNP) or phenylephrine (Phe). Brainstem slices were submitted to immunohistochemistry and immunofluorescence. After 6-OHDA injection, 75% of the dopaminergic neurons in the SNc were absent, confirming establishment of the PD model. Intravenous (iv) injection of SNP generated reduced hypotension and tachycardia response, and the noncatecholaminergic (nonC1) neurons of the rostral ventrolateral medulla (RVLM) were less activated. Additionally, iv injection of Phe increased blood pressure and bradycardia to the same extent and activated equivalent numbers of neurons in the nucleus of the solitary tract and the caudal ventrolateral medulla as well as cholinergic neurons of the dorsal motor nucleus of the vagus and the nucleus ambiguus between control and PD animals. In summary, these data showed that in the PD model, impairment of cardiovascular autonomic control was observed only during deactivation of the baroreflex, which could be related to reduced activation of non-C1 neurons within the RVLM.
Effects of selective inhibition of nNOS and iNOS on neuropathic pain in rats
Molecular and Cellular Neuroscience, Volume 105, 2020, Article 103497
Various animal models have been employed to understand the pathogenic mechanism of neuropathic pain. Nitric oxide (NO) is an important molecule in nociceptive transmission and is involved in neuropathic pain. However, its mechanistic actions remain unclear. The aim of this study was to better understand the involvement of neuronal and inducible isoforms of nitric oxide synthase (nNOS and iNOS) in neuropathic pain induced by chronic constriction injury (CCI) of the sciatic nerve in rats. We evaluated pain sensitivity (mechanical withdrawal thresholds using Randall and Selitto, and von Frey tests, and thermal withdrawal thresholds using Hargreaves test) prior to CCI surgery, 14days post CCI and after intrathecal injections of selective nNOS or iNOS inhibitors. We also evaluated the distribution of NOS isozymes in the spinal cord and dorsal root ganglia (DRG) by immunohistochemistry, synthesis of iNOS and nNOS by Western blot, and NO production using fluorescent probe DAF-2 DA (DA). Our results showed higher number of nNOS and iNOS-positive neurons in the spinal cord and DRG of CCI compared to sham rats, and their reduction in CCI rats after treatment with selective inhibitors compared to non-treated groups. Western blot results also indicated reduced expression of nNOS and iNOS after treatment with selective inhibitors. Furthermore, both inhibitors reduced CCI-evoked mechanical and thermal withdrawal thresholds but only nNOS inhibitor was able to efficiently lower mechanical withdrawal thresholds using von Frey test. In addition, we observed higher NO production in the spinal cord and DRG of injured rats compared to control group. Our study innovatively shows that nNOS may strongly modulate nociceptive transmission in rats with neuropathic pain, while iNOS may partially participate in the development of nociceptive responses. Thus, drugs targeting nNOS for neuropathic pain may represent a potential therapeutic strategy.
Hypoxic ventilatory response after dopamine D2 receptor blockade in unilateral rat model of Parkinson’s disease
Neuroscience, Volume 316, 2016, pp. 192-200
Modified non-motor brainstem ventilatory control might be involved in Parkinson’s disease. Our study was designed to investigate the impact of degeneration of the nigrostriatal dopaminergic pathway on resting breathing and hypoxic ventilatory response in conscious rats. The role of central and peripheral dopamine D2 receptors in the modulation of the hypoxic ventilatory response in conditions of dopamine shortage was examined. Adult Wistar rats received a unilateral double 6-hydroxydopamine lesion of the right medial forebrain bundle. After surgery, animals were placed in whole-body plethysmographic chamber and exposed to hypoxia (8% O2). One group of animals received inraperitoneal injections of either haloperidol or domperidone before hypoxia. Levels of dopamine and its metabolite in the brainstem and striatum were assessed. Neurotoxin treatment evoked limb use asymmetry. No effect on the resting normoxic respiration was observed. An increase in tidal volume and a decrease in respiratory rate during respiratory response to hypoxia with short magnification of minute ventilation were predominant effects. Domperidone treatment in intact animals evoked a significant increase in normoxic tidal volume, while haloperidol potentiated tidal volume increase in response to hypoxia. After the lesion, the effects of both antagonists were absent. In rats with Parkinson’s, the content of dopamine and its metabolite decreased substantially in the injured striatum. Augmentation of a tidal volume response to hypoxia, and the absence of stimulatory effect of intraperitoneal domperidone on normoxic and haloperidol on hypoxic tidal volume, in lesioned rats indicated altered control of breathing. This could be the result of a dopamine deficiency in the striatum and an increased turnover of DOPAC/DA in the brainstem.
Orexinergic neurons are involved in the chemosensory control of breathing during the dark phase in a Parkinson's disease model
Experimental Neurology, Volume 309, 2018, pp. 107-118
Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra compacta (SNpc) and the only risk factor is aging. We showed that in 6-hydroxydopamine (6-OHDA)-model of PD there is a reduction in the neuronal profile within the brainstem ventral respiratory column with a decrease in the hypercapnic ventilatory response. Here we tested the involvement of orexin cells from the lateral hypothalamus/perifornical area (LH/PeF) on breathing in a 6-OHDA PD model. In this model of PD, there is a reduction in the total number of orexinergic neurons and in the number of orexinergic neurons that project to the RTN, without changing the number of CO2-activated orexinergic neurons during the dark phase. The ventilation at rest and in response to hypercapnia (7% CO2) was assessed in animals that received 6-OHDA or vehicle injections into the striatum and saporin anti-Orexin-B or IgG saporin into the LH/PeF during the sleep and awake states. The experiments showed a reduction of respiratory frequency (fR) at rest during the light phase in PD animals only during sleep. During the dark phase, there was an impaired fR response to hypercapnia in PD animals with depletion of orexinergic neurons in awake and sleeping rats. In conclusion, the degeneration of orexinergic neurons in this model of PD can be related to impaired chemoreceptor function in the dark phase.
Altered adenosine 2A and dopamine D2 receptor availability in the 6-hydroxydopamine-treated rats with and without levodopa-induced dyskinesia
NeuroImage, Volume 157, 2017, pp. 209-218
Several lines of evidence imply alterations in adenosine signaling in Parkinson's disease (PD). Here, we investigated cerebral changes in adenosine 2A receptor (A2AR) availability in 6-hydroxydopamine (6-OHDA)-lesioned rats with and without levodopa-induced dyskinesia (LID) using positron-emission tomography (PET) with [11C]preladenant. In parallel dopamine type 2 receptor (D2R) imaging with [11C]raclopride PET and behavioral tests for motor and cognitive function were performed.
Parametric A2AR and D2R binding potential (BPND) images were reconstructed using reference tissue models with midbrain and cerebellum as reference tissue, respectively. All images were anatomically standardized to Paxinos space and analyzed using volume-of-interest (VOI) and voxel-based approaches. The behavioral alternations were assessed with the open field test, Y-maze, novel object recognition test, cylinder test, and abnormal involuntary movement (AIM) score. In total, 28 female Wistar rats were included.
On the behavioral level, 6-OHDA-lesioned rats showed asymmetry in forepaw use and deficits in spatial memory and explorative behavior as compared to the sham-operated animals. 15-Days of levodopa (L-DOPA) treatment induced dyskinesia but did not alleviate motor deficits in PD rats. Intranigral 6-OHDA injection significantly increased D2R binding in the lesioned striatum (BPND: 2.69 ± 0.40 6-OHDA vs. 2.31 ± 0.18 sham, + 16.6%; p = 0.03), whereas L-DOPA treatment did not affect the D2R binding in the ipsilateral striatum of the PD rats. In addition, intranigral 6-OHDA injection tended to decrease the A2AR availability in the lesioned striatum. The decrease became significant when data were normalized to the non-affected side (BPND: 4.32 ± 0.41 6-OHDA vs. 4.58 ± 0.89 sham; NS, ratio: 0.94 ± 0.03 6-OHDA vs. 1.00 ± 0.02 sham; − 6.1%; p = 0.01). L-DOPA treatment significantly increased A2AR binding in the affected striatum (BPND: 6.02 ± 0.91 L-DOPA vs. 4.90 ± 0.76 saline; + 23.4%; p = 0.02). In PD rats with LID, positive correlations were found between D2R and A2AR BPND values in the ipsilateral striatum (r = 0.88, ppeak = 8.56.10−4 uncorr), and between AIM score and the D2R BPND in the contralateral striatum (r = 0.98; ppeak = 9.55.10−5 uncorr).
A2AR availability changed in drug-naïve and in L-DOPA-treated PD rats. The observed correlations of striatal D2R availability with A2AR availability and with AIM score may provide new knowledge on striatal physiology and new possibilities to further unravel the functions of these targets in the pathophysiology of PD.
Cardiovascular dysfunction associated with neurodegeneration in an experimental model of Parkinson’s disease
Brain Research, Volume 1657, 2017, pp. 156-166
Patients with Parkinson’s disease (PD) exhibit both motor and non-motor symptoms. Among the non-motor symptoms, cardiovascular autonomic dysfunction is frequently observed. Here, we evaluated baroreflex function, vascular reactivity and neuroanatomical changes in brainstem regions involved in the neural control of circulation in the 6-hydroxydopamine (6-OHDA) model of PD. Male Wistar rats received a bilateral injection of 6-OHDA or vehicle into the striatum. After 61days, baroreflex function and vascular reactivity were assessed. The 6-OHDA and vehicle groups showed similar increases in mean arterial pressure (MAP) in response to phenylephrine (PE). However, the bradycardia observed in the vehicle group was blunted in the 6-OHDA-treated rats. Injection of sodium nitroprusside (SNP) decreased hypotension, tachycardia and vascular relaxation in 6-OHDA-treated rats. Bilateral intrastriatal 6-OHDA led to massive degeneration of tyrosine hydroxylase (TH)-immunoreactive neurons in the substantia nigra and to reductions in the numbers of A1/C1 and A5 catecholaminergic neurons while sparing A2 neurons within the nucleus of the solitary tract (NTS). 6-OHDA-treated rats also showed decreases in Phox2b-expressing neurons in the NTS and in choline acetyltransferase (ChAT) immunoreactivity in the nucleus ambiguus. Altogether, our data suggest that this model of PD includes neuroanatomical and functional changes that lead to cardiovascular impairment.
These authors contributed equally to this study, as student supervisors.
© 2019 Elsevier B.V. All rights reserved.