Nonmotor Symptoms in Experimental Models of Parkinson's Disease

Titova, Nataliya; Schapira, Anthony H. V.; Qamar, Mubasher A; Katunina, E A; Jenner, Peter

doi:10.1016/bs.irn.2017.05.018

Cited by 26 publications

(18 citation statements)

References 98 publications

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“…Using the forced swimming test, control rats subchronically treated with L-DOPA and fluoxetine showed reduced efficacy of the antidepressant drug, while coadministration of the NET blocker reboxetine and L-DOPA provided the opposite effect (Miguelez et al, 2013). At the behavioral level, regardless inconsistencies found through the scientific publications, p a r k i n s o n i a n a n i m a l s t e n d t o m i m i c t h e h u m a n symptomatology showing motor but also non-motor impairments (Titova et al, 2017). An array of studies report that rodents lesioned with 6-OHDA or MPTP show anxious and depressive behavior, pain, cognitive, and sleep disturbances (Monaca et al, 2004;Pérez et al, 2009;Berghauzen-Maciejewska et al, 2014;Vo et al, 2014;Kamińska et al, 2017;Charles et al, 2018;Campos et al, 2019;Domenici et al, 2019), more notably in bilateral models of the disease (Ferro et al, 2005;Tadaiesky et al, 2008;Santiago et al, 2010;Bonito-Oliva et al, 2014;Vieira et al, 2019).…”

Section: Preclinical Evidencementioning

confidence: 98%

The Noradrenergic System in Parkinson’s Disease

et al. 2020

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Nowadays it is well accepted that in Parkinson's disease (PD), the neurodegenerative process occurs in stages and that damage to other areas precedes the neuronal loss in the substantia nigra pars compacta, which is considered a pathophysiological hallmark of PD. This heterogeneous and progressive neurodegeneration may explain the diverse symptomatology of the disease, including motor and non-motor alterations. In PD, one of the first areas undergoing degeneration is the locus coeruleus (LC). This noradrenergic nucleus provides extensive innervation throughout the brain and plays a fundamental neuromodulator role, participating in stress responses, emotional memory, and control of motor, sensory, and autonomic functions. Early in the disease, LC neurons suffer modifications that can condition the effectiveness of pharmacological treatments, and importantly, can lead to the appearance of common non-motor symptomatology. The noradrenergic system also exerts anti-inflammatory and neuroprotective effect on the dopaminergic degeneration and noradrenergic damage can consequently condition the progress of the disease. From the pharmacological point of view, it is also important to understand how the noradrenergic system performs in PD, since noradrenergic medication is often used in these patients, and drug interactions can take place when combining them with the gold standard drug therapy in PD, L-3,4-dihydroxyphenylalanine (L-DOPA). This review provides an overview about the functional status of the noradrenergic system in PD and its contribution to the efficacy of pharmacologicalbased treatments. Based on preclinical and clinical publications, a special attention will be dedicated to the most prevalent non-motor symptoms of the disease.

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Section: Preclinical Evidencementioning

confidence: 98%

The Noradrenergic System in Parkinson’s Disease

et al. 2020

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“…Normally the concept of APD is underpinned by a progressive loss of nigrostriatal dopaminergic terminals which eventually disables the buffering capacity to manage fluctuations in striatal dopamine levels (Obeso 2008 ; Poewe 2010 ). But it is clear that there is also considerable loss of other neurotransmitter based neurons, sometimes even greater than the dopaminergic loss, leading to the complex syndromic nature of PD (Korczyn 1999 ; Langston 2006 ; Titova et al 2017b ). Specifically, the gastrointestinal tract involvement at a cellular and molecular level is now well recognised and gastrointestinal dysfunction common across all stages of PD may lead to erratic/delayed gastric emptying.…”

Section: Introductionmentioning

confidence: 99%

Advanced Parkinson’s or “complex phase” Parkinson’s disease? Re-evaluation is needed

et al. 2017

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Holistic management of Parkinson’s disease, now recognised as a combined motor and nonmotor disorder, remains a key unmet need. Such management needs relatively accurate definition of the various stages of Parkinson’s from early untreated to late palliative as each stage calls for personalised therapies. Management also needs to have a robust knowledge of the progression pattern and clinical heterogeneity of the presentation of Parkinson’s which may manifest in a motor dominant or nonmotor dominant manner. The “advanced” stages of Parkinson’s disease qualify for advanced treatments such as with continuous infusion or stereotactic surgery yet the concept of “advanced Parkinson’s disease” (APD) remains controversial in spite of growing knowledge of the natural history of the motor syndrome of PD. Advanced PD is currently largely defined on the basis of consensus opinion and thus with several caveats. Nonmotor aspects of PD may also reflect advancing course of the disorder, so far not reflected in usual scale based assessments which are largely focussed on motor symptoms. In this paper, we discuss the problems with current definitions of “advanced” PD and also propose the term “complex phase” Parkinson’s disease as an alternative which takes into account a multimodal symptoms and biomarker based approach in addition to patient preference.

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“…In this study, animals were shown to exhibit an enhanced response to psychostimulants (DOI-induced head twitches and amphetamine-induced hypercolocomotion), as well as a deficit in acoustic prepulse inhibition. Other models, such as MPTP-lesioned primates, have been developed and, quite interestingly, psychotic-like behaviour was observed in this type of model only after dopaminergic drug treatment (Titova et al, 2017;Visanji et al, 2006).…”

Section: Accepted Manuscriptmentioning

confidence: 99%

“…Other studies in 6-hydroxydopamine (6-OHDA)-lesioned rats have also reported that chronic L-dopa may worsen lesion-induced anxiety and depression (Eskow Jaunarajs et al, 2010, while it has been recently suggested that chronic L-dopa treatment per se could induce depression-like behaviour, anhedonia and cognitive dysfunction in unlesioned rats, with Fos induction and DA receptor dysregulation in the hippocampus (Hernández et al, 2014). Finally, the fact that MPTP-lesioned primates show psychotic-like behaviour only after dopaminergic drug treatment (Titova et al, 2017) is also in line with this idea of a possible major impact of repeated DRT exposure on the onset of neuropsychiatric complications.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Implication of nigral dopaminergic lesion and repeated L-dopa exposure in neuropsychiatric symptoms of Parkinson’s disease

Loiodice¹,

Young²,

Rion³

et al. 2019

Behavioural Brain Research

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This study aims to investigate the contribution of nigral dopaminergic (DA) cell loss, repeated exposure to DA medication and the combination of both to the development of neuropsychiatric symptoms observed in Parkinson's disease (PD). A bilateral 6-OHDA lesion of the substantia nigra pars compacta (SNc) was performed in rats. A set of animals was repeatedly administered with L-dopa (20 mg/kg/day) and benserazide (5 mg/kg/day) over 10 days starting from day 11 post-lesion. Behavioural testing was performed in week 3 postlesion: novel object recognition (NOR), elevated plus maze (EPM) social interaction (SI) tests, and amphetamine-induced hyperlocomotion (AIH). Immunohistochemical analysis revealed a significant partial lesion (48%) in 6-OHDA versus sham rats. This lesion was not associated with motor impairment. However, lesioned rats displayed a significant deficit in the NOR, which was reversed by acute treatment with L-dopa/benserazide (12.5 mg/kg and 15 mg/kg respectively). Lesioned rats also displayed a deficit in the EPM which was not reversed by acute treatment with L-dopa. No difference was observed in the SI test or in the AIH assay. In all assays, no effect of chronic L-dopa exposure was observed. This study provides new insights into the neuropathophysiology associated with neuropsychiatric symptoms of PD. Our data strongly emphasises a not previously clearly identified critical role in cognition for the SNc. The results suggest that DA pathways were less directly involved in lesioninduced anxiety-like behaviour. We did not report any effect of chronic L-dopa exposure in the context of partial nigral cell loss.

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Nonmotor Symptoms in Experimental Models of Parkinson's Disease

Cited by 26 publications

References 98 publications

The Noradrenergic System in Parkinson’s Disease

The Noradrenergic System in Parkinson’s Disease

Advanced Parkinson’s or “complex phase” Parkinson’s disease? Re-evaluation is needed

Implication of nigral dopaminergic lesion and repeated L-dopa exposure in neuropsychiatric symptoms of Parkinson’s disease

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