Cholinergic muscarinic M1 and M4 receptors as therapeutic targets for cognitive, behavioural, and psychological symptoms in psychiatric and neurological disorders

Erskine, Daniel; Taylor, John-Paul; Bakker, Geor; Brown, Alastair; Tasker, Tim; Nathan, Pradeep J.

doi:10.1016/j.drudis.2019.08.009

Cited by 38 publications

(25 citation statements)

References 73 publications

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“…It has been suggested that regions with particularly high energy demands would render some cellular populations particularly vulnerable to degeneration, secondary to mitochondrial deficits [39]. Therefore, the present study reporting mitochondrial respiratory chain deficits in the nbM, a region whose cells have high energy demands and are also susceptible to Lewy body pathology and significant cell loss [8], is consistent with the hypothesis that regions with high energy demands are vulnerable to neuronal loss and mitochondrial dysfunction in LBD.…”

Section: Discussionsupporting

confidence: 91%

“…ChAT catalyses the production of acetylcholine from acetyl-CoA, a key enzyme for mitochondrial energy production [38] and, as ChAT expression is thought to be proportionate to the rate of acetylcholine synthesis and substrate availability [38], one could speculate that the observed elevations in ChAT in the iLBD group reflect higher levels of acetylcholine and acetyl-CoA. Elevations in acetylcholine synthesis and acetyl-CoA expression in iLBD cases could be a plausible explanation for preserved respiratory chain expression and cognitive capacity in iLBD cases, given that the abundance of acetyl-CoA reflects the general energetic state of a cell [31] and acetylcholine has critical roles in higher cognitive processes that are compromised in LBD [8]. However, it should be emphasised that it is difficult to draw strong conclusions when the iLBD cohort only comprised two patients.…”

Section: Discussionmentioning

confidence: 99%

“…LBD is a collective term for dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), which are clinically distinguished on the basis of the temporal onset of symptoms, with cognitive symptoms preceding or occurring concurrently with motor symptoms in DLB whereas motor symptoms are a presenting feature of PDD [24]. DLB is marked by particularly accelerated cognitive decline, even compared to AD [16], yet there is an absence of therapies that can offer anything but modest symptomatic treatment [8]. Therefore, there is a pressing need to better understand the mechanisms that underlie cognitive impairment in LBD in the hope that these may contribute to the development of disease-modifying therapies.…”

Section: Introductionmentioning

confidence: 99%

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Complex I reductions in the nucleus basalis of Meynert in Lewy body dementia: the role of Lewy bodies

Hatton

Reeve

Lax

et al. 2020

acta neuropathol commun

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Neurons of the nucleus basalis of Meynert (nbM) are vulnerable to Lewy body formation and neuronal loss, which is thought to underlie cognitive dysfunction in Lewy body dementia (LBD). There is continued debate about whether Lewy bodies exert a neurodegenerative effect by affecting mitochondria, or whether they represent a protective mechanism. Therefore, the present study sought to determine whether the nbM is subject to mitochondrial dysfunctional in LBD and the association of Lewy body formation with such changes. Post-mortem nbM tissue was stained for Complex I or IV and quantitated relative to porin with immunofluorescence using confocal microscopy of individual cells from LBD (303 neurons, 8 cases), control (362 neurons, 8 cases) and asymptomatic incidental LBD (iLBD) cases (99 neurons, 2 cases). Additionally, αsynuclein, tau and amyloid-β pathology were analysed using quantitative immunohistochemistry, and respiratory chain markers were compared in cells with Lewy bodies (N = 134) and unaffected cells (N = 272). The expression of Complex I normalised to mitochondrial mass was significantly lower in LBD compared to control and iLBD cases and this was unrelated to local neuropathological burdens but trended toward a relationship with neuronal loss. Furthermore, Complex I expression was higher in cells with Lewy bodies compared to adjacent cells without α-synuclein aggregates. These findings suggest that Complex I deficits in the nbM occur in symptomatic LBD cases and may relate to neuronal loss, but that contrary to the view that Lewy body formation underlies neuronal dysfunction and damage in LBD, Lewy bodies are associated with higher Complex I expression than neurons without Lewy bodies. One could speculate that Lewy bodies may provide a mechanism to encapsulate damaged mitochondria and/or α-synuclein oligomers, thus protecting neurons from their cytotoxic effects.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Complex I reductions in the nucleus basalis of Meynert in Lewy body dementia: the role of Lewy bodies

Hatton

Reeve

Lax

et al. 2020

acta neuropathol commun

Self Cite

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“…Muscarinic acetylcholine receptor antagonists have been in clinical use for decades to treat such diverse conditions as Parkinson's disease, peptic ulcers, overactive bladder, chronic obstructive pulmonary disease, asthma and motion sickness, with specific drug use depending on muscarinic receptor sub-type selectivity and tissue accessibility (Kruse et al, 2014). Despite the widely studied and pharmacologically manipulated role of muscarinic receptors in modulating synaptic function in the central (Erskine et al, 2019;Moran et al, 2019) and autonomic (Giglio and Tobin, 2009;Tobin et al, 2009) nervous systems, it has only recently become apparent that peripheral sensory neurons maintained in vitro after extraction from adult rodents experience tonic cholinergic suppression of maximal mitochondrial respiratory capacity and neurite outgrowth (Calcutt et al, 2017). Inhibition of the M 1 sub-type of the muscarinic receptor (M 1 R), which is expressed by adult sensory neurons, is critical to these effects as neurite outgrowth from sensory neuron cultures derived from adult rodents is increased by M 1 R knockout and by diverse M 1 R specific and selective antagonists.…”

Section: Introductionmentioning

confidence: 99%

Topical Delivery of Muscarinic Receptor Antagonists Prevents and Reverses Peripheral Neuropathy in Female Diabetic Mice

Jolivalt¹,

Frizzi²,

Han³

et al. 2020

J Pharmacol Exp Ther

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Muscarinic antagonists promote sensory neurite outgrowth in vitro and prevent and/or reverse multiple indices of peripheral neuropathy in rodent models of diabetes, chemotherapy-induced peripheral neuropathy and HIV protein-induced neuropathy when delivered systemically. We measured plasma concentrations of the M 1 receptor selective muscarinic antagonist pirenzepine when delivered by sub-cutaneous injection, oral gavage or topical application to the skin and investigated efficacy of topically delivered pirenzepine against indices of peripheral neuropathy in diabetic mice. Topical application of 2% pirenzepine to the paw resulted in plasma concentrations 6hr postdelivery that approximated those previously shown to promote neurite outgrowth in vitro. Topical delivery of pirenzepine to the paw of streptozotocin-diabetic mice dosedependently (0.1-10.0%) prevented tactile allodynia, thermal hypoalgesia and loss of epidermal nerve fibers in the treated paw and attenuated large fiber motor nerve conduction slowing in the ipsilateral limb. Efficacy against some indices of neuropathy was also noted in the contralateral limb, indicating systemic effects following local treatment. Topical pirenzepine also reversed established paw heat hypoalgesia while withdrawal of treatment resulted in a gradual decline in efficacy over 2-4 weeks. Efficacy of topical pirenzepine was muted when treatment was reduced from 5 to 3 or 1 days per week. Similar local effects were noted with the non-selective muscarinic receptor antagonist atropine when applied either to the paw or to the eye. Topical delivery of muscarinic antagonists may serve as a practical therapeutic approach to treating diabetic and other peripheral neuropathies.

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“…Of the five muscarinic receptor subtypes, xanomeline exhibits selectivity for the M1 and M4 receptors (Shannon et al, 2000;Andersen et al, 2003;Mirza et al, 2003). An increasing body of preclinical and clinical evidence has highlighted a potential beneficial effect of cholinergic stimulation on brain disorders characterized by cognitive dysfunction or psychosis, including neurodegenerative conditions such as Alzheimer disease or neuropsychiatric diseases such as schizophrenia (Felder et al, 2018;Verma et al, 2018;Erskine et al, 2019). These properties have prompted clinical investigations into the use of this drug to improve cognitive function and behavioral disturbance in Alzheimer's disease patients, with encouraging results but dose-limiting peripheral cholinergic side effects (Avery et al, 1997;NC et al, 1997;Cui et al, 2008;Si et al, 2010;Wang et al, 2011;Melancon et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

The M1/M4 agonist xanomeline modulates functional connectivity and NMDAR antagonist-induced changes in the mouse brain

Montani

Canella

Schwarz

et al. 2020

Preprint

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Cholinergic drugs acting at M1/M4 muscarinic receptors hold promise for the treatment of symptoms associated with brain disorders characterized by cognitive impairment, mood disturbances or psychosis, such as Alzheimer's disease or schizophrenia. However, the brain-wide functional substrates engaged by muscarinic agonists remain poorly understood. Here we used a combination of pharmacological fMRI (phMRI), resting-state fMRI (rsfMRI) and resting-state quantitative EEG (qEEG) to investigate the effects of a behaviorally-active dose of M1/M4 agonist xanomeline on brain functional activity in the rodent brain. We investigated both the effects of xanomeline per se and its modulatory effects on signals elicited by the NMDA-receptor antagonists phencyclidine (PCP) and ketamine. We found that xanomeline induces robust and widespread BOLD signal phMRI amplitude increases and decreased high frequency qEEG spectral activity. rsfMRI mapping in the mouse revealed that xanomeline robustly decreased neocortical and striatal connectivity but induces focal increases in functional connectivity within the nucleus accumbens and basal forebrain. Notably, xanomeline pre-administration robustly attenuated both the cortico-limbic phMRI response and the fronto-hippocampal hyper-connectivity induced by PCP, enhanced PCP-modulated functional connectivity locally within the nucleus accumbens and basal forebrain, and reversed the gamma and high frequency qEEG power increases induced by ketamine. Collectively, these results show that xanomeline robustly induces both cholinergic-like neocortical activation and desynchronization of functional networks in the mammalian brain. These effects could serve as a translatable biomarker for future clinical investigations of muscarinic agents, and bear mechanistic relevance for the putative therapeutic effect of these class of compounds in brain disorders.

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Cholinergic muscarinic M1 and M4 receptors as therapeutic targets for cognitive, behavioural, and psychological symptoms in psychiatric and neurological disorders

Cited by 38 publications

References 73 publications

Complex I reductions in the nucleus basalis of Meynert in Lewy body dementia: the role of Lewy bodies

Complex I reductions in the nucleus basalis of Meynert in Lewy body dementia: the role of Lewy bodies

Topical Delivery of Muscarinic Receptor Antagonists Prevents and Reverses Peripheral Neuropathy in Female Diabetic Mice

The M1/M4 agonist xanomeline modulates functional connectivity and NMDAR antagonist-induced changes in the mouse brain

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