Anticholinergic Drugs and Amantadine in the Treatment of Parkinson’s Disease

Lang, Anthony E.; Blair, R. D. G.

doi:10.1007/978-3-642-73899-9_12

Cited by 21 publications

(13 citation statements)

References 73 publications

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“…Regardless of the source of ACh that contributes to the expression or treatment of specific symptoms of movement disorders, our data suggest that ChI or PPN sources of ACh acting through M 4 may be an exciting target to relieve certain symptoms of movement disorders. Our data showing M 4 has multiple actions to oppose DA release and signaling in the BG are especially interesting in light of the established efficacy of nonselective mAChR antagonists . This raises the possibility that compounds selectively and specifically targeting M 4 may be able to maintain the efficacy of broad‐spectrum antimuscarinic therapeutics while avoiding the severe adverse effects.…”

Section: Mechanisms Of M4 Activity In the Bgmentioning

confidence: 86%

“…The use of antimuscarinic agents, namely trihexyphenidyl, has a long‐established efficacy in reducing specific motor symptoms of PD and dystonia . In addition, trihexyphenidyl, and other poorly selective or nonselective antimuscarinic compounds, are effective at reducing abnormal movements in animal models of dystonia and PD with overt motor deficits .…”

Section: Mechanisms Of M4 Activity In the Bgmentioning

confidence: 99%

“…The use of antimuscarinic agents, namely trihexyphenidyl, has a long-established efficacy in reducing specific motor symptoms of PD and dystonia. 16,[62][63][64][65] In addition, trihexyphenidyl, and other poorly selective or nonselective antimuscarinic compounds, are effective at reducing abnormal movements in animal models of dystonia and PD with overt motor deficits. [66][67][68] The efficacy of antimuscarinic compounds both preclinically and clinically suggest that mAChRs are important regulators of certain symptom domains of movement disorders.…”

Section: Antimuscarinic Therapy Is Efficacious In Treating Movement Dmentioning

confidence: 99%

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Roles of the M₄ acetylcholine receptor in the basal ganglia and the treatment of movement disorders

Moehle

Conn

2019

Movement Disorders

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Acetylcholine (ACh) released from cholinergic interneurons acting through nicotinic and muscarinic acetylcholine receptors (mAChRs) in the striatum have been thought to be central for the potent cholinergic regulation of basal ganglia activity and motor behaviors. ACh activation of mAChRs has multiple actions to oppose dopamine (DA) release, signaling, and related motor behaviors and has led to the idea that a delicate balance of DA and mAChR signaling in the striatum is critical for maintaining normal motor function. Consistent with this, mAChR antagonists have efficacy in reducing motor symptoms in diseases where DA release or signaling is diminished, such as in Parkinson's disease and dystonia, but are limited in their utility because of severe adverse effects. Recent breakthroughs in understanding both the anatomical sites of action of ACh and the mAChR subtypes involved in regulating basal ganglia function reveal that the M4 subtype plays a central role in regulating DA signaling and release in the basal ganglia. These findings have raised the possibility that sources of ACh outside of the striatum can regulate motor activity and that M4 activity is a potent regulator of motor dysfunction. We discuss how M4 activity regulates DA release and signaling, the potential sources of ACh that can regulate M4 activity, and the implications of targeting M4 activity for the treatment of the motor symptoms in movement disorders. © 2019 International Parkinson and Movement Disorder Society

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Section: Mechanisms Of M4 Activity In the Bgmentioning

confidence: 86%

Section: Mechanisms Of M4 Activity In the Bgmentioning

confidence: 99%

Section: Antimuscarinic Therapy Is Efficacious In Treating Movement Dmentioning

confidence: 99%

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Roles of the M₄ acetylcholine receptor in the basal ganglia and the treatment of movement disorders

Moehle

Conn

2019

Movement Disorders

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“…1 In 1867, Ordenstein first reported their antiparkinsonian effect, which Charcot had discovered fortuitously when administering tinctures of deadly nightshade (Atropa belladonna) for excessive salivation in parkinsonian patients. 2 For almost a century, anticholinergics remained the only possible treatment for parkinsonism. At first, a variety of naturally occurring solanaceous alkaloids were used, often administered in the form of wine extracts (Bulgarian belladonna) or cigarettes.…”

Section: Introduction Backgroundmentioning

confidence: 99%

Anticholinergic therapies in the treatment of Parkinson's disease

2002

Mov Disord.

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“…Early studies suggested that amantadine may be an indirect DA agonist by augmenting the synthesis and reducing the uptake of DA (Lang and Blair, 1989). However, nowadays it is generally believed that amantadine exerts its beneficial effects through uncompetitive inhibition of NMDA receptor (NMDAr) (Danysz et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Amantadine protects dopamine neurons by a dual action: Reducing activation of microglia and inducing expression of GNDF in astroglia

et al. 2011

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Amantadine is commonly given to alleviate L-DOPA-induced dyskinesia of Parkinson’s disease (PD) patients. Animal and human evidence showed that amantadine may also exert neuroprotection in several neurological disorders. Additionally, it is generally believed that this neuroprotection results from the ability of amantadine to inhibit glutamatergic NMDA receptor. However, several lines of evidence questioned the neuroprotection capacity of NMDA receptor antagonists in animal models of PD. Thus the cellular and molecular mechanism of neuroprotection of amantadine remains unclear. Using primary cultures with different composition of neurons, microglia, and astroglia we investigated the direct role of these different glial cell types in the neuroprotective effect of amantadine. First, amantadine protected rat midbrain cultures from either MPP+ or lipopolysaccharide (LPS), two toxins commonly used PD models. Second, our studies revealed that amantadine reduced both LPS- and MPP+ -induced toxicity of dopamine neuron through 1) the inhibition of the release of microglial pro-inflammatory factors, 2) an increase in expression of neurotrophic factor such as GDNF from astroglia. Lastly, differently from the general view on amantadine´s action, we provided evidence suggesting that NMDA receptor inhibition was not crucial for the neuroprotective effect of amantadine. In conclusion, we report that amantadine protected dopamine neurons in two PD models through a novel dual mechanism, namely reducing the release of pro-inflammatory factors from activated microglia and increasing the expression of GNDF in astroglia.

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Anticholinergic Drugs and Amantadine in the Treatment of Parkinson’s Disease

Cited by 21 publications

References 73 publications

Roles of the M₄ acetylcholine receptor in the basal ganglia and the treatment of movement disorders

Roles of the M₄ acetylcholine receptor in the basal ganglia and the treatment of movement disorders

Anticholinergic therapies in the treatment of Parkinson's disease

Amantadine protects dopamine neurons by a dual action: Reducing activation of microglia and inducing expression of GNDF in astroglia

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Anticholinergic Drugs and Amantadine in the Treatment of Parkinson’s Disease

Cited by 21 publications

References 73 publications

Roles of the M4 acetylcholine receptor in the basal ganglia and the treatment of movement disorders

Roles of the M4 acetylcholine receptor in the basal ganglia and the treatment of movement disorders

Anticholinergic therapies in the treatment of Parkinson's disease

Amantadine protects dopamine neurons by a dual action: Reducing activation of microglia and inducing expression of GNDF in astroglia

Contact Info

Product

Resources

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Roles of the M₄ acetylcholine receptor in the basal ganglia and the treatment of movement disorders

Roles of the M₄ acetylcholine receptor in the basal ganglia and the treatment of movement disorders