l-DOPA-induced dyskinesia and neuroinflammation: do microglia and astrocytes play a role?

Carta, A. R., Mulas, G., Bortolanza, M., Duarte, T., Pillai, E., Fisone, G., Vozari, R. R. and Del-Bel, E. (2017), 

Eur J Neurosci, 45: 73–91. doi:10.1111/ejn.13482

In Parkinson's disease (PD), l-DOPA therapy leads to the emergence of motor complications including l-DOPA-induced dyskinesia (LID). LID relies on a sequence of pre- and postsynaptic neuronal events, leading to abnormal corticostriatal neurotransmission and maladaptive changes in striatal projection neurons. In recent years, additional non-neuronal mechanisms have been proposed to contribute to LID. Among these mechanisms, considerable attention has been focused on l-DOPA-induced inflammatory responses. Microglia and astrocytes are the main actors in neuroinflammatory responses, and their double role at the interface between immune and neurophysiological responses is starting to be elucidated. Both microglia and astrocytes express a multitude of neurotransmitter receptors and via the release of several soluble molecules modulate synaptic function in neuronal networks. Here we review preclinical and clinical evidence of glial overactivation by l-DOPA, supporting a role of microglia and astrocytes in the development of LID. We propose that in PD, chronically and abnormally activated microglia and astrocytes lead to an aberrant neuron-glia communication, which affect synaptic activity and neuroplasticity contributing to the development of LID.

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Pathological gambling in Parkinson's disease: what are the risk factors and what is the role of impulsivity?

Heiden, P., Heinz, A. and Romanczuk-Seiferth, N. (2017), 

Eur J Neurosci, 45: 67–72. doi:10.1111/ejn.13396

The incidence of pathological gambling in Parkinson's patients is significantly greater than in the general population. A correlation has been observed between dopamine agonist medication and the development of pathological gambling. However, scientists conjecture that the affected patients have underlying risk factors. Studies analysing Parkinson's patients have detected that patients who developed pathological gambling are younger, score higher on novelty-seeking tests, are more impulsive and are more likely to have a personal or family history of alcohol addiction. In addition, some genetic variations have been associated with the susceptibility of developing pathological gambling, which include mutations of DRD3, 5-HTTLPR and GRIN2B. Studies focusing on neurofunctional discrepancies between Parkinson's patients with and without pathological gambling have found increased functional activation and dopamine release in regions associated with the mesolimbic reward system. Furthermore, there is also evidence showing increased processing of reward and decreased activation elicited by punishment, suggesting altered learning processes. Furthermore, the role of deep brain stimulation of the nucleus subthalamicus (STN DBS) is controversial. In most Parkinson's patients, pathological gambling resolved after the initiation of the STN DBS, which might be explained by discontinuation or decrease in dopamine agonist medication. However, it has been also shown that some patients are more impulsive while the STN DBS is activated. These differences may depend on the DBS localization in the more limbic or motor part of the STN and their regulative effects on impulsivity. Further research is needed to clarify susceptibility factors for the development of pathological gambling in Parkinson's patients.

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Dopamine and noradrenaline, but not serotonin, in the human claustrum are greatly reduced in patients with Parkinson's disease: possible functional implications.

Sitte, H. H., Pifl, C., Rajput, A. H., Hörtnagl, H., Tong, J., Lloyd, G. K., Kish, S. J. and Hornykiewicz, O. (2017), 

Eur J Neurosci, 45: 192–197. doi:10.1111/ejn.13435

In the human brain, the claustrum is a small subcortical telencephalic nucleus, situated between the insular cortex and the putamen. A plethora of neuroanatomical studies have shown the existence of dense, widespread, bidirectional and bilateral monosynaptic interconnections between the claustrum and most cortical areas. A rapidly growing body of experimental evidence points to the integrative role of claustrum in complex brain functions, from motor to cognitive. Here, we examined for the first time, the behaviour of the classical monoamine neurotransmitters dopamine, noradrenaline and serotonin in the claustrum of the normal autopsied human brain and of patients who died with idiopathic Parkinson's disease (PD). We found in the normal claustrum substantial amounts of all three monoamine neurotransmitters, substantiating the existence of the respective brain stem afferents to the claustrum. In PD, the levels of dopamine and noradrenaline were greatly reduced by 93 and 81%, respectively. Serotonin levels remained unchanged. We propose that by virtue of their projections to the claustrum, the brain stem dopamine, noradrenaline and serotonin systems interact directly with the cortico-claustro-cortical information processing mechanisms, by-passing their (parallel) routes via the basal ganglia-thalamo-cortical circuits. We suggest that loss of dopamine and noradrenaline in the PD claustrum is critical in the aetiology of both the motor and the non-motor symptoms of PD.

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Membrane transporters as mediators of synaptic dopamine dynamics: implications for disease.

Lohr, K. M., Masoud, S. T., Salahpour, A. and Miller, G. W. (2017), 

Eur J Neurosci, 45: 20–33. doi:10.1111/ejn.13357

Dopamine was first identified as a neurotransmitter localized to the midbrain over 50 years ago. The dopamine transporter (DAT; SLC6A3) and the vesicular monoamine transporter 2 (VMAT2; SLC18A2) are regulators of dopamine homeostasis in the presynaptic neuron. DAT transports dopamine from the extracellular space into the cytosol of the presynaptic terminal. VMAT2 then packages this cytosolic dopamine into vesicular compartments for subsequent release upon neurotransmission. Thus, DAT and VMAT2 act in concert to move the transmitter efficiently throughout the neuron. Accumulation of dopamine in the neuronal cytosol can trigger oxidative stress and neurotoxicity, suggesting that the proper compartmentalization of dopamine is critical for neuron function and risk of disease. For decades, studies have examined the effects of reduced transporter function in mice (e.g. DAT-KO, VMAT2-KO, VMAT2-deficient). However, we have only recently been able to assess the effects of elevated transporter expression using BAC transgenic methods (DAT-tg, VMAT2-HI mice). Complemented with in vitro work and neurochemical techniques to assess dopamine compartmentalization, a new focus on the importance of transporter proteins as both models of human disease and potential drug targets has emerged. Here, we review the importance of DAT and VMAT2 function in the delicate balance of neuronal dopamine.

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Combination of alpha-synuclein immunotherapy with anti-inflammatory treatment in a transgenic mouse model of multiple system atrophy

By Jensflorian - Own work, CC BY-SA 3.0,
https://commons.wikimedia.org/w/index.php?curid=11787560

Valera E, Spencer B, Jerel A. Fields, Ivy Trinh, Anthony Adame, Michael Mante, Edward Rockenstein, Paula Desplats and Eliezer Masliah 

Acta Neuropathologica Communications Neuroscience of Disease 20175:2

Multiple system atrophy (MSA) is a fatal neurodegenerative disorder characterized by the pathological accumulation of alpha-synuclein (α-syn) in oligodendrocytes. Therapeutic efforts to stop or delay the progression of MSA have yielded suboptimal results in clinical trials, and there are no efficient treatments currently available for MSA patients. We hypothesize that combining therapies targeting different aspects of the disease may lead to better clinical outcomes. To test this hypothesis, we combined the use of a single-chain antibody targeting α-syn modified for improved central nervous system penetration (CD5- 5) with an unconventional anti-inflammatory treatment (lenalidomide) in the myelin basic protein (MBP)-α-syn transgenic mouse model of MSA. While the use of either CD5-D5 or lenalidomide alone had positive effects on neuroinflammation and/or α-syn accumulation in this mouse model of MSA, the combination of both approaches yielded better results than each single treatment. The combined treatment reduced astrogliosis, microgliosis, soluble and aggregated α-syn levels, and partially improved behavioral deficits in MBP-α-syn transgenic mice. These effects were associated with an activation of the Akt signaling pathway, which may mediate cytoprotective effects downstream tumor necrosis factor alpha (TNFα). These results suggest that a strategic combination of treatments may improve the therapeutic outcome in trials for MSA and related neurodegenerative disorders.

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Parkinson's disease - causes, symptoms, diagnosis, treatment & pathology

Movement signs and symptoms of Parkinson's disease | NCLEX-RN | Khan Aca...

Caffeine alleviates progressive motor deficits in a transgenic mouse model of spinocerebellar ataxia.

Gonçalves N, Simões AT, Prediger RS, Hirai H, Cunha RA, Pereira de Almeida L;Ann Neurol. 2016 Dec 29;:

OBJECTIVE: Machado-Joseph disease (MJD) is a neurodegenerative spinocerebellar ataxia (SCA) associated with an expanded polyglutamine tract within ataxin-3 for which there is currently no available therapy. We previously showed that caffeine, a non-selective adenosine receptor antagonist, delays the appearance of striatal damage resulting from expression of full-length mutant ataxin-3. Here we investigated the ability of caffeine to alleviate behavioral deficits and cerebellar neuropathology in transgenic mice with a severe ataxia resulting from expression of a truncated fragment of polyglutamine-expanded ataxin-3 in Purkinje cells.
METHODS: Control and transgenic c57Bl6 mice expressing in the mouse cerebella a truncated form of human ataxin-3 with 69 glutamine repeats, were allowed to freely drink water or caffeine (1 g/L). Treatments began at 7 weeks of age, when motor and ataxic phenotype emerges in MJD mice, and lasted up to 20 weeks. Mice were tested in a panel of locomotor behavioral paradigms, namely rotarod, beam balance and walking, pole and water maze cued-platform version tests and then sacrificed for cerebellar histology.
RESULTS: Caffeine consumption attenuated the progressive loss of general and fine-tuned motor function, balance and grip strength, in parallel with a preservation of cerebellar morphology through decreasing the loss of Purkinje neurons and the thinning of the molecular layer in different folia. Caffeine also rescued the putative striatal-dependent executive and cognitive deficiencies in MJD mice.
INTERPRETATION: Our findings provide the first in vivo demonstration that caffeine intake alleviates behavioral disabilities in a severely impaired animal model of SCA. This article is protected by copyright. All rights reserved.

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