The mGluR5 positive allosteric modulator, CDPPB, ameliorates pathology and phenotypic signs of a mouse model of Huntington's disease

Doria, Juliana G.; Souza, Jéssica M. de; Andrade, Jéssica Neves; Rodrigues, Hermann A.; Guimaraes, Isabella M; Carvalho, Toniana G.; Guatimosim, Cristina; Dobránsky, Tomàš; Ribeiro, Fabíola M.

doi:10.1016/j.nbd.2014.08.021

Cited by 45 publications

(58 citation statements)

References 45 publications

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“…11B). Postsynaptic mGlu 5 positively modulate NMDAR and mGlu 5 PAMs have been shown to rescue NMDAR-dependent synaptic plasticity and behavior in autism and Huntington models (Won et al, 2012;Doria et al, 2015). We found that CDPPB restored LTP in the n-3-deficient group (Fig.…”

Section: N-3 Pufa Deficiency Impairs Ecb-mediated Plasticity In the Asupporting

confidence: 53%

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Amplification of mGlu₅-Endocannabinoid Signaling Rescues Behavioral and Synaptic Deficits in a Mouse Model of Adolescent and Adult Dietary Polyunsaturated Fatty Acid Imbalance

et al. 2017

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Energy-dense, yet nutritionally poor food is a high-risk factor for mental health disorders. This is of particular concern during adolescence, a period often associated with increased consumption of low nutritional content food and higher prevalence of mental health disorders. Indeed, there is an urgent need to understand the mechanisms linking unhealthy diet and mental disorders. Deficiency in n-3 polyunsaturated fatty acids (PUFAs) is a hallmark of poor nutrition and mood disorders. Here, we developed a mouse model of n-3 PUFA deficiency lasting from adolescence into adulthood. Starting nutritional deficits in dietary n-3 PUFAs during adolescence decreased n-3 PUFAs in both medial prefrontal cortex (mPFC) and nucleus accumbens, increased anxiety-like behavior, and decreased cognitive function in adulthood. Importantly, we discovered that endocannabinoid/mGlu 5 -mediated LTD in the mPFC and accumbens was abolished in adult n-3-deficient mice. Additionally, mPFC NMDAR-dependent LTP was also lacking in the n-3-deficient group. Pharmacological enhancement of the mGlu 5 /eCB signaling complex, by positive allosteric modulation of mGlu 5 or inhibition of endocannabinoid 2-arachidonylglycerol degradation, fully restored synaptic plasticity and normalized emotional and cognitive behaviors in malnourished adult mice. Our data support a model where nutrition is a key environmental factor influencing the working synaptic range into adulthood, long after the end of the perinatal period. These findings have important implications for the identification of nutritional risk factors for disease and design of new treatments for the behavioral deficits associated with nutritional n-3 PUFA deficiency.

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Section: N-3 Pufa Deficiency Impairs Ecb-mediated Plasticity In the Asupporting

confidence: 53%

“…Modulators of mGlu 5 receptors may be useful in the treatment of neuropsychiatric disease (Belzung, 2001;Won et al, 2012;Doria et al, 2015). In the n-3-deficient group, social cognition and temporal order memory (Fig.…”

Section: Potentiation Of Mglu 5 Rescues Cognitive and Emotional Behavmentioning

confidence: 99%

Amplification of mGlu₅-Endocannabinoid Signaling Rescues Behavioral and Synaptic Deficits in a Mouse Model of Adolescent and Adult Dietary Polyunsaturated Fatty Acid Imbalance

et al. 2017

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“…CDPPB and VU29 were included as structurally distinct allosteric modulators from the same chemotype class, where CDPPB has been reported to be a PAM-agonist and VU29 a ‘pure’ PAM (Chen et al, 2007; Lindsley et al, 2004). CDPPB has previously been tested in vivo , showing efficacy in models of Huntington’s disease, fear extinction, psychosis and addiction (Cleva et al, 2011; Doria et al, 2015; Ganella et al, 2014; Gass et al, 2014; Uslaner et al, 2009). Recently, VU0409551 was described as a biased modulator on the basis that VU0409551 positively modulates mGlu 5 activity in vitro but does not enhance mGlu 5 modulation of NMDA current or NMDA receptor dependent plasticity in the hippocampus (Rook et al, 2015).…”

Section: Resultsmentioning

confidence: 99%

Biased allosteric agonism and modulation of metabotropic glutamate receptor 5: Implications for optimizing preclinical neuroscience drug discovery

et al. 2017

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Allosteric modulators, that exhibit no intrinsic agonist activity, offer the advantage of spatial and temporal fine-tuning of endogenous agonist activity, allowing the potential for increased selectivity, reduced adverse effects and improved clinical outcomes. Some allosteric ligands can differentially activate and/or modulate distinct signaling pathways arising from the same receptor, phenomena referred to as ’biased agonism’ and ’biased modulation’. Emerging evidence for CNS disorders with glutamatergic dysfunction suggests the metabotropic glutamate receptor subtype 5 (mGlu5) is a promising target. Current mGlu5 allosteric modulators have largely been classified based on modulation of intracellular calcium (iCa2+) responses to orthosteric agonists alone. We assessed eight mGlu5 allosteric modulators previously classified as mGlu5 PAMs or PAM-agonists representing four distinct chemotypes across multiple measures of receptor activity, to explore their potential for engendering biased agonism and/or modulation. Relative to the reference orthosteric agonist, DHPG, the eight allosteric ligands exhibited distinct biased agonism fingerprints for iCa2+ mobilization, IP1 accumulation and ERK1/2 phosphorylation in HEK293A cells stably expressing mGlu5 and in cortical neuron cultures. VU0424465, DPFE and VU0409551 displayed the most disparate biased signaling fingerprints in both HEK293A cells and cortical neurons that may account for the marked differences observed previously for these ligands in vivo. Select mGlu5 allosteric ligands also showed ‘probe dependence’ with respect to their cooperativity with different orthosteric agonists, as well as biased modulation for the magnitude of positive cooperativity observed. Unappreciated biased agonism and modulation may contribute to unanticipated effects (both therapeutic and adverse) when translating from recombinant systems to preclinical models.

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“…Cognitive impairment, in addition to motor abnormalities, is another important clinical characteristic of HD patients38. We performed the object recognition test to verify whether W20 treatment could improve the cognitive function in BACHD mice.…”

Section: Resultsmentioning

confidence: 99%

A scFv antibody targeting common oligomeric epitope has potential for treating several amyloidoses

Zha

Liu

Zhu

et al. 2016

Sci Rep

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Overproduction or poor clearance of amyloids lead to amyloid aggregation and even amyloidosis development. Different amyloids may interact synergistically to promote their aggregation and accelerate pathology in amyloidoses. Amyloid oligomers assembled from different amyloids share common structures and epitopes, and are considered the most toxic species in the pathologic processes of amyloidoses, which suggests that an agent targeting the common epitope of toxic oligomers could provide benefit to several amyloidoses. In this study, we firstly showed that an oligomer-specific single-chain variable fragment antibody, W20 simultaneously improved motor and cognitive function in Parkinson’s disease and Huntington’s disease mouse models, and attenuated a number of neuropathological features by reducing α-synuclein and mutant huntingtin protein aggregate load and preventing synaptic degeneration. Neuroinflammation and oxidative stress in vivo were also markedly inhibited. The proposed strategy targeting the common epitopes of amyloid oligomers presents promising potential for treating Parkinson’s disease, Huntington’s disease, Alzheimer’s disease, and other amyloidoses.

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The mGluR5 positive allosteric modulator, CDPPB, ameliorates pathology and phenotypic signs of a mouse model of Huntington's disease

Cited by 45 publications

References 45 publications

Amplification of mGlu₅-Endocannabinoid Signaling Rescues Behavioral and Synaptic Deficits in a Mouse Model of Adolescent and Adult Dietary Polyunsaturated Fatty Acid Imbalance

Amplification of mGlu₅-Endocannabinoid Signaling Rescues Behavioral and Synaptic Deficits in a Mouse Model of Adolescent and Adult Dietary Polyunsaturated Fatty Acid Imbalance

Biased allosteric agonism and modulation of metabotropic glutamate receptor 5: Implications for optimizing preclinical neuroscience drug discovery

A scFv antibody targeting common oligomeric epitope has potential for treating several amyloidoses

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The mGluR5 positive allosteric modulator, CDPPB, ameliorates pathology and phenotypic signs of a mouse model of Huntington's disease

Cited by 45 publications

References 45 publications

Amplification of mGlu5-Endocannabinoid Signaling Rescues Behavioral and Synaptic Deficits in a Mouse Model of Adolescent and Adult Dietary Polyunsaturated Fatty Acid Imbalance

Amplification of mGlu5-Endocannabinoid Signaling Rescues Behavioral and Synaptic Deficits in a Mouse Model of Adolescent and Adult Dietary Polyunsaturated Fatty Acid Imbalance

Biased allosteric agonism and modulation of metabotropic glutamate receptor 5: Implications for optimizing preclinical neuroscience drug discovery

A scFv antibody targeting common oligomeric epitope has potential for treating several amyloidoses

Contact Info

Product

Resources

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Amplification of mGlu₅-Endocannabinoid Signaling Rescues Behavioral and Synaptic Deficits in a Mouse Model of Adolescent and Adult Dietary Polyunsaturated Fatty Acid Imbalance

Amplification of mGlu₅-Endocannabinoid Signaling Rescues Behavioral and Synaptic Deficits in a Mouse Model of Adolescent and Adult Dietary Polyunsaturated Fatty Acid Imbalance