Animal models of Parkinson's disease (PD) have proved highly effective in the discovery of novel treatments for motor symptoms of PD and in the search for clues to the underlying cause of the ...illness. Models based on specific pathogenic mechanisms may subsequently lead to the development of neuroprotective agents for PD that stop or slow disease progression. The array of available rodent models is large and ranges from acute pharmacological models, such as the reserpine‐ or haloperidol‐treated rats that display one or more parkinsonian signs, to models exhibiting destruction of the dopaminergic nigro‐striatal pathway, such as the classical 6‐hydroxydopamine (6‐OHDA) rat and 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) mouse models. All of these have provided test beds in which new molecules for treating the motor symptoms of PD can be assessed. In addition, the emergence of abnormal involuntary movements (AIMs) with repeated treatment of 6‐OHDA‐lesioned rats with L‐DOPA has allowed for examination of the mechanisms responsible for treatment‐related dyskinesia in PD, and the detection of molecules able to prevent or reverse their appearance. Other toxin‐based models of nigro‐striatal tract degeneration include the systemic administration of the pesticides rotenone and paraquat, but whilst providing clues to disease pathogenesis, these are not so commonly used for drug development. The MPTP‐treated primate model of PD, which closely mimics the clinical features of PD and in which all currently used anti‐parkinsonian medications have been shown to be effective, is undoubtedly the most clinically‐relevant of all available models. The MPTP‐treated primate develops clear dyskinesia when repeatedly exposed to L‐DOPA, and these parkinsonian animals have shown responses to novel dopaminergic agents that are highly predictive of their effect in man. Whether non‐dopaminergic drugs show the same degree of predictability of response is a matter of debate. As our understanding of the pathogenesis of PD has improved, so new rodent models produced by agents mimicking these mechanisms, including proteasome inhibitors such as PSI, lactacystin and epoximycin or inflammogens like lipopolysaccharide (LPS) have been developed. A further generation of models aimed at mimicking the genetic causes of PD has also sprung up. Whilst these newer models have provided further clues to the disease pathology, they have so far been less commonly used for drug development. There is little doubt that the availability of experimental animal models of PD has dramatically altered dopaminergic drug treatment of the illness and the prevention and reversal of drug‐related side effects that emerge with disease progression and chronic medication. However, so far, we have made little progress in moving into other pharmacological areas for the treatment of PD, and we have not developed models that reflect the progressive nature of the illness and its complexity in terms of the extent of pathology and biochemical change. Only when this occurs are we likely to make progress in developing agents to stop or slow the disease progression. The overarching question that draws all of these models together in the quest for better drug treatments for PD is how well do they recapitulate the human condition and how predictive are they of successful translation of drugs into the clinic? This article aims to clarify the current position and highlight the strengths and weaknesses of available models.
LINKED ARTICLES This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue‐4
Current drugs used in the treatment of Parkinson's disease (PD), for example, L‐DOPA and dopamine agonists, are very effective at reversing the motor symptoms of the disease. However, they do little ...to combat the underlying degeneration of dopaminergic neurones in the substantia nigra pars compacta (SNc) and their long‐term use is associated with the appearance of adverse effects such as L‐DOPA‐induced dyskinesia. Much emphasis has therefore been placed on finding alternative non‐dopaminergic drugs that may circumvent some or all of these problems. Group III metabotropic glutamate (mGlu) receptors were first identified in the basal ganglia a decade ago. One or more of these receptors (mGlu4, mGlu7 or mGlu8) is found on pre‐synaptic terminals of basal ganglia pathways whose overactivity is implicated not only in the generation of motor symptoms in PD, but also in driving the progressive SNc degeneration. The finding that drugs which activate group III mGlu receptors can inhibit transmission across these overactive synapses has lead to the proposal that group III mGlu receptors are promising targets for drug discovery in PD. This paper provides a comprehensive review of the role and target potential of group III mGlu receptors in the basal ganglia. Overwhelming evidence obtained from in vitro studies and animal models of PD supports group III mGlu receptors as potentially important drug targets for providing both symptom relief and neuroprotection in PD.
In this review, we discuss the most recent evidence on mechanisms underlying pathological nociceptive processing in Parkinson's disease patients, as well as novel treatment strategies.
In Parkinson's ...disease, specific neurodegenerative changes may cause alterations in nociceptive processing at multiple levels. Optimization of dopaminergic therapies should always be the first step in the management of Parkinson's disease pain. Reportedly, rotigotine transdermal patch, a monoamine oxidase type B inhibitor safinamide (as an add-on therapy to levodopa), subcutaneous apomorphine and intrajejunal levodopa infusion therapy may have a beneficial effect on pain sensations in Parkinson's disease patients. Among the nondopaminergic pharmacological therapies, prolonged-release oxycodone/naloxone and duloxetine may be effective in the treatment of chronic pain in Parkinson's disease. Botulinum toxin (BTX) injections should be considered for the treatment of dystonic Parkinson's disease pain. Deep brain stimulation (DBS) may lead to pain relief with a long-lasting effect in Parkinson's disease patients. Physiotherapy and physical activity in general are essential for Parkinson's disease patients suffering from pain.
Pain in Parkinson's disease is not simply a consequence of motor complainants. The management of Parkinson's disease-related pain implicates maintenance of stable levels of dopaminergic drugs. Nondopaminergic pharmacological therapies (prolonged-release oxycodone/naloxone, duloxetine, BTX) and nonpharmacological interventions (DBS, physiotherapie) may also be beneficial in treatment of Parkinson's disease pain.
Glutamate plays a complex role in many aspects of Parkinson’s disease including the loss of dopaminergic neurons, the classical motor symptoms as well as associated non-motor symptoms and the ...treatment-related side effect,
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-DOPA-induced dyskinesia. This widespread involvement opens up possibilities for glutamate-based therapies to provide a more rounded approach to treatment than is afforded by current dopamine replacement therapies. Beneficial effects of blocking postsynaptic glutamate transmission have already been noted in a range of preclinical studies using antagonists of NMDA receptors or negative allosteric modulators of metabotropic glutamate receptor 5 (mGlu5), while positive allosteric modulators of mGlu4 in particular, although at an earlier stage of investigation, also look promising. This review addresses each of the key features of Parkinson’s disease in turn, summarising the contribution glutamate makes to that feature and presenting an up-to-date account of the potential for drugs acting at ionotropic or metabotropic glutamate receptors to provide relief. Whilst only a handful of these have progressed to clinical trials to date, notably NMDA and NR2B antagonists against motor symptoms and
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-DOPA-induced dyskinesia, with mGlu5 negative allosteric modulators also against
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-DOPA-induced dyskinesia, the mainly positive outcomes of these trials, coupled with supportive preclinical data for other strategies in animal models of Parkinson’s disease and
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-DOPA-induced dyskinesia, raise cautious optimism that a glutamate-based therapeutic approach will have significant impact on the treatment of Parkinson’s disease.
A mixed-methods randomized controlled trial pilot study evaluated an educational curriculum focused on the medical needs of transition-age youth (TAY) with autism (ASD) for family nurse practitioner ...students. Fourteen out of a cohort of 16 (87.5%) nursing students consented to participate in the study and were randomly assigned to either a waitlist control group (WLC) (n = 8) or an intervention group (INT) (n = 6). Three measures were used to determine pre- and post-intervention levels of self-efficacy, knowledge, and attitudes. Quantitative and qualitative data provide preliminary support that participation in intervention may improve and enhance knowledge and level of self-efficacy in working with TAY with ASD.
Pain is a common non-motor symptom of Parkinson`s disease (PD), however, its pathomechanism remains elusive. We aimed to investigate the local gene expression of selected proinflammatory mediators in ...patients with PD and correlated our data with patients`pain phenotype. We recruited 30 patients with PD and 30 healthy controls. Pain intensity of patients was assessed using the Numeric Rating Scale (NRS) and patients were stratified into PD pain (NRSgreater than or equal to4) and PD No Pain (NRS<4) subgroups. Skin punch biopsies were immunoassayed for protein-gene product 9.5 as a pan-neuronal marker and intraepidermal nerve fiber density (IEFND). Quantitative real-time polymerase chain reaction (qRT-PCR) analysis was performed to assess the gene expression of inflammatory mediators in the skin compared to controls. Our data suggest the occurrence of a local, peripheral inflammatory response in the skin in PD, but do not support this being a relevant factor contributing to pain in PD.
Phthalates are multifunctional chemicals used in a variety of applications, including personal care products. The present study explored the relationship between patterns of personal care product use ...and urinary levels of several phthalate metabolites. Subjects include 406 men who participated in an ongoing semen quality study at the Massachusetts General Hospital Andrology Laboratory between January 2000 and February 2003. A nurse-administered questionnaire was used to determine use of personal care products, including cologne, aftershave, lotions, hair products, and deodorants. Phthalate monoester concentrations were measured in a single spot urine sample by isotope dilution-high-performance liquid chromatography coupled to tandem mass spectrometry. Men who used cologne or aftershave within 48 hr before urine collection had higher median levels of monoethyl phthalate (MEP) (265 and 266 ng/mL, respectively) than those who did not use cologne or aftershave (108 and 133 ng/mL, respectively). For each additional type of product used, MEP increased 33% (95% confidence interval, 14-53%). The use of lotion was associated with lower urinary levels of monobutyl phthalate (MBP) (14.9 ng/mL), monobenzyl phthalate (MBzP) (6.1 ng/mL), and mono(2-ethylhexyl) phthalate (MEHP) (4.4 ng/mL) compared with men who did not use lotion (MBP, 16.8 ng/mL; MBzP, 8.6 ng/mL; MEHP, 7.2 ng/mL). The identification of personal care products as contributors to phthalate body burden is an important step in exposure characterization. Further work in this area is needed to identify other predictors of phthalate exposure.
Pain is a key non-motor feature of Parkinson's disease (PD) that significantly impacts on life quality. The mechanisms underlying chronic pain in PD are poorly understood, hence the lack of effective ...treatments. Using the 6-hydroxydopamine (6-OHDA) lesioned rat model of PD, we identified reductions in dopaminergic neurons in the periaqueductal grey (PAG) and Met-enkephalin in the dorsal horn of the spinal cord that were validated in human PD tissue samples. Pharmacological activation of D
-like receptors in the PAG, identified as the DRD5
phenotype located on glutamatergic neurons, alleviated the mechanical hypersensitivity seen in the Parkinsonian model. Downstream activity in serotonergic neurons in the Raphé magnus (RMg) was also reduced in 6-OHDA lesioned rats, as detected by diminished c-FOS positivity. Furthermore, we identified increased pre-aggregate α-synuclein, coupled with elevated activated microglia in the dorsal horn of the spinal cord in those people that experienced PD-related pain in life. Our findings have outlined pathological pathways involved in the manifestation of pain in PD that may present targets for improved analgesia in people with PD.
Background: Phthalates are multifunctional chemicals used in a variety of consumer, medical, and personal care products. Previously, we reported dose-response associations of decreased semen quality ...with urinary concentrations of monobutyl phthalate (MBP) and monobenzyl (MBzP) phthalate, which are metabolites of dibutyl phthalate and butylbenzyl phthalate, respectively. The present study extends our work in a larger sample of men and includes measurements of di(2-ethylhexyl) phthalate (DEHP) oxidative metabolites. Methods: Between January 2000 and May 2004, we recruited 463 male partners of subfertile couples who presented for semen analysis to the Massachusetts General Hospital. Semen parameters were dichotomized based on World Health Organization reference values for sperm concentration (<20 million/mL) and motility (<50% motile) and the Tygerberg Kruger Strict criteria for morphology (<4% normal). The comparison group was men with all 3 semen parameters above the reference values. In a single spot urine sample from each man, phthalate metabolites were measured using solid-phase extraction coupled to high-performance liquid chromatography isotope-dilution tandem mass spectrometry. Results: There were dose-response relationships of MBP with low sperm concentration (odds ratio per quartile adjusted for age, abstinence time, and smoking status = 1.00, 3.1, 2.5, 3.3; P for trend = 0.04) and motility (1.0, 1.5, 1.5, 1.8; P for trend = 0.04). There was suggestive evidence of an association between the highest MBzP quartile and low sperm concentration (1.00, 1.1, 1.1, 1.9; P for trend = 0.13). There were no relationships of monoethyl phthalate, monomethyl phthalate, and the DEHP metabolites with these semen parameters. Conclusion: The present study confirms previous results on the relationship of altered semen quality with exposure to MBP at general population levels. We did not find associations between semen parameters and 3 DEHP metabolites.
Pain is a commonly occurring non-motor symptom of Parkinson's disease (PD). Treatment of pain in PD remains less than optimal and a better understanding of the underlying mechanisms would facilitate ...discovery of improved analgesics. Animal models of PD have already proven helpful for furthering the understanding and treatment of motor symptoms of PD, but could these models offer insight into pain in PD? This review addresses the current position regarding pain in preclinical models of PD, covering the face and predictive validity of existing models and their use so far in advancing understanding of the mechanisms contributing to pain in PD. While pain itself is not usually measured in animals, nociception in the form of thermal, mechanical or chemical nociceptive thresholds offers a useful readout, given reduced nociceptive thresholds are commonly seen in PD patients. Animal models of PD including the reserpine-treated rat and neurodegenerative models such as the MPTP-treated mouse and 6-hydroxydopamine (6-OHDA)-treated rat each exhibit reduced nociceptive thresholds, supporting face validity of these models. Furthermore, some interventions known clinically to relieve pain in PD, such as dopaminergic therapies and deep brain stimulation of the subthalamic nucleus, restore nociceptive thresholds in one or more models, supporting their predictive validity. Mechanistic insight gained already includes involvement of central and spinal dopamine and opioid systems. Moving forward, these preclinical models should advance understanding of the cellular and molecular mechanisms underlying pain in PD and provide test beds for examining the efficacy of novel analgesics to better treat this debilitating non-motor symptom.
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