Role of pedunculopontine cholinergic neurons in the vulnerability of nigral dopaminergic neurons in Parkinson's disease

Bensaïd, Manale; Michel, Patrick P.; Clark, Stewart D.; Hirsch, Étienne C.; François, Chantal

doi:10.1016/j.expneurol.2015.11.004

Cited by 39 publications

(39 citation statements)

References 61 publications

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“…3,4 In contrast, neuronal loss in nonmelanized brain regions appears either inconsistent, not specific to PD, or secondary to the loss of interconnected neuromelanin-containing neurons. [5][6][7] In the normal human midbrain, dopamine-producing cell groups markedly differ from each other in terms of…”

Section: Neuromelanin and Pd: A 100-year-old Relationshipmentioning

confidence: 99%

Neuromelanin, aging, and neuronal vulnerability in Parkinson's disease

Vila

2019

Movement Disorders

107

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Neuromelanin, a dark brown intracellular pigment, has long been associated with Parkinson's disease (PD). In PD, neuromelanin‐containing neurons preferentially degenerate, tell‐tale neuropathological inclusions form in close association with this pigment, and neuroinflammation is restricted to neuromelanin‐containing areas. In humans, neuromelanin accumulates with age, which in turn is the main risk factor for PD. The potential contribution of neuromelanin to PD pathogenesis remains unknown because, in contrast to humans, common laboratory animals lack neuromelanin. The recent introduction of a rodent model exhibiting an age‐dependent production of human‐like neuromelanin has allowed, for the first time, for the consequences of progressive neuromelanin accumulation—up to levels reached in elderly human brains—to be assessed in vivo. In these animals, intracellular neuromelanin accumulation above a specific threshold compromises neuronal function and triggers a PD‐like pathology. As neuromelanin levels reach this threshold in PD patients and presymptomatic PD patients, the modulation of neuromelanin accumulation could provide a therapeutic benefit for PD patients and delay brain aging. © 2019 The Author. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

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Section: Neuromelanin and Pd: A 100-year-old Relationshipmentioning

confidence: 99%

Neuromelanin, aging, and neuronal vulnerability in Parkinson's disease

Vila

2019

Movement Disorders

107

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“…In turn, degeneration of PPN cholinergic and glutamatergic cells projecting to the nigral dopamine neurons would contribute to nigral dopamine cell loss. Studies in rat and monkey indicate that destruction of dopamine cells causes degeneration of MLR cholinergic cells (Pienaar et al, 2015b; Bensaid et al, 2016). Conversely, lesion of PPN cholinergic neurons induces a loss of dopaminergic nigral neurons (Bensaid et al, 2016).…”

Section: Possible Role Of the Descending Dopaminergic Pathway In Pdmentioning

confidence: 99%

“…Studies in rat and monkey indicate that destruction of dopamine cells causes degeneration of MLR cholinergic cells (Pienaar et al, 2015b; Bensaid et al, 2016). Conversely, lesion of PPN cholinergic neurons induces a loss of dopaminergic nigral neurons (Bensaid et al, 2016). Finally, lesion of nigral dopaminergic neurons followed by lesion of PPN cholinergic cells induces a more dramatic degeneration of PPN cholinergic cells (Bensaid et al, 2016), suggesting that the two lesions interact to create a transneuronal degeneration loop.…”

Section: Possible Role Of the Descending Dopaminergic Pathway In Pdmentioning

confidence: 99%

“…Conversely, lesion of PPN cholinergic neurons induces a loss of dopaminergic nigral neurons (Bensaid et al, 2016). Finally, lesion of nigral dopaminergic neurons followed by lesion of PPN cholinergic cells induces a more dramatic degeneration of PPN cholinergic cells (Bensaid et al, 2016), suggesting that the two lesions interact to create a transneuronal degeneration loop. Stabilization of the reciprocal interactions between dopamine and cholinergic neurons could be a promising avenue to alleviate degeneration of the two systems.…”

Section: Possible Role Of the Descending Dopaminergic Pathway In Pdmentioning

confidence: 99%

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Dopamine and the Brainstem Locomotor Networks: From Lamprey to Human

2017

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In vertebrates, dopamine neurons are classically known to modulate locomotion via their ascending projections to the basal ganglia that project to brainstem locomotor networks. An increased dopaminergic tone is associated with increase in locomotor activity. In pathological conditions where dopamine cells are lost, such as in Parkinson's disease, locomotor deficits are traditionally associated with the reduced ascending dopaminergic input to the basal ganglia. However, a descending dopaminergic pathway originating from the substantia nigra pars compacta was recently discovered. It innervates the mesencephalic locomotor region (MLR) from basal vertebrates to mammals. This pathway was shown to increase locomotor output in lampreys, and could very well play an important role in mammals. Here, we provide a detailed account on the newly found dopaminergic pathway in lamprey, salamander, rat, monkey, and human. In lampreys and salamanders, dopamine release in the MLR is associated with the activation of reticulospinal neurons that carry the locomotor command to the spinal cord. Dopamine release in the MLR potentiates locomotor movements through a D1-receptor mechanism in lampreys. In rats, stimulation of the substantia nigra pars compacta elicited dopamine release in the pedunculopontine nucleus, a known part of the MLR. In a monkey model of Parkinson's disease, a reduced dopaminergic innervation of the brainstem locomotor networks was reported. Dopaminergic fibers are also present in human pedunculopontine nucleus. We discuss the conserved locomotor role of this pathway from lamprey to mammals, and the hypothesis that this pathway could play a role in the locomotor deficits reported in Parkinson's disease.

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“…Dysfunctional acetylcholine signaling is associatedwith significant pathological conditions (eg, Alzheimer's disease [1] , Parkinson's disease [2][3][4][5] and schizophrenia [6][7][8] ). Its cholinergic effects are mediated through either muscarinic (mAChR) or nicotinic (nAChR) receptors.…”

Section: Introductionmentioning

confidence: 99%

Discovery, synthesis, biological evaluation and structure-based optimization of novel piperidine derivatives as acetylcholine-binding protein ligands

Shen

Yang

et al. 2016

Acta Pharmacol Sin

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The homomeric α7 nicotinic receptor (α7 nAChR) is widely expressed in the human brain that could be activated to suppress neuroinflammation, oxidative stress and neuropathic pain. Consequently, a number of α7 nAChR agonists have entered clinical trials as anti-Alzheimer's or anti-psychotic therapies. However, high-resolution crystal structure of the full-length α7 receptor is thus far unavailable. Since acetylcholine-binding protein (AChBP) from Lymnaea stagnalis is most closely related to the α-subunit of nAChRs, it has been used as a template for the N-terminal domain of α-subunit of nAChR to study the molecular recognition process of nAChRligand interactions, and to identify ligands with potential nAChR-like activities. Here we report the discovery and optimization of novel acetylcholine-binding protein ligands through screening, structure-activity relationships and structure-based design. We manually screened in-house CNS-biased compound library in vitro and identified compound 1, a piperidine derivative, as an initial hit with moderate binding affinity against AChBP (17.2% inhibition at 100 nmol/L). During the 1st round of optimization, with compound 2 (21.5% inhibition at 100 nmol/L) as the starting point, 13 piperidine derivatives with different aryl substitutions were synthesized and assayed in vitro. No apparent correlation was demonstrated between the binding affinities and the steric or electrostatic effects of aryl substitutions for most compounds, but compound 14 showed a higher affinity (K i =105.6 nmol/L) than nicotine (K i =777 nmol/L). During the 2nd round of optimization, we performed molecular modeling of the putative complex of compound 14 with AChBP, and compared it with the epibatidine-AChBP complex. The results suggested that a different piperidinyl substitution might confer a better fit for epibatidine as the reference compound. Thus, compound 15 was designed and identified as a highly affinitive acetylcholinebinding protein ligand. In this study, through two rounds of optimization, compound 15 (K i =2.8 nmol/L) has been identified as a novel, piperidine-based acetylcholine-binding protein ligand with a high affinity.

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Role of pedunculopontine cholinergic neurons in the vulnerability of nigral dopaminergic neurons in Parkinson's disease

Cited by 39 publications

References 61 publications

Neuromelanin, aging, and neuronal vulnerability in Parkinson's disease

Neuromelanin, aging, and neuronal vulnerability in Parkinson's disease

Dopamine and the Brainstem Locomotor Networks: From Lamprey to Human

Discovery, synthesis, biological evaluation and structure-based optimization of novel piperidine derivatives as acetylcholine-binding protein ligands

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