The adenosine Areceptor agonist T1-11 ameliorates neurovisceral symptoms and extends the lifespan of a mouse model of Niemann-Pick type C disease

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Abstract

Niemann-Pick C is a fatal neurovisceral disorder caused, in 95% of cases, by mutation of NPC1 gene. Therapeutic options are extremely limited and new "druggable" targets are highly warranted. We previously demonstrated that the stimulation of the adenosine A2Areceptor (A2AR) normalized the pathological phenotype of cellular models of NPC1. Since the validation of A2ARs as a therapeutic target for NPC1 can be obtained only conducting studies in in vivo models of the disease, in the present paper, the effects of two agonists of A2ARs were evaluated in the mouse model Balb/c Npc1nih, hereafter indicated as NPC1-/-. The agonists CGS21680 (2.5 and 5mg/kg/day by intraperitoneal injection) and T1-11 (50mg/kg/day in drinking water) were administered at a presymptomatic stage of the disease of NPC1-/- mice (PN28 and PN30, respectively); the experimental groups were the following: vehicle-treated WT mice (N=16 for both CGS and T1-11 treatments); vehicle-treated NPC1-/- mice (N=14 for CGS and 12 for T1-11 treatment); CGS-treated NPC1-/- mice (N=7) and T1-11-treated NPC1-/- mice (N=11). The efficacy of the treatments was evaluated by comparing vehicle-treated and CGS or T1-11-treated NPC1-/- mice for their motor deficits (analyzed by both rotarod and footprint tests), hippocampal cognitive impairment (by Novel Object Recognition (NOR) test), cerebellar neurodegeneration (Purkinje neurons counting), and cholesterol and sphingomyelin accumulation in spleen and liver. Finally, the effect of both agonists on survival was evaluated by applying a humane late endpoint (weight loss >30% of peak weight, punched posture and reduced activity in the cage). The results demonstrated that, while CGS21680 only slightly attenuated cognitive deficits, T1-11 ameliorated motor coordination, significantly improved cognitive impairments, increased the survival of Purkinje neurons and reduced sphingomyelin accumulation in the liver. More importantly, it significantly prolonged the lifespan of NPC1-/- mice. In vitro experiments conducted in a neuronal model of NPC1 demonstrated that the ability of T1-11 to normalize cell phenotype was mediated by the selective activation of A2ARs and modulation of intracellular calcium levels. In conclusion, our results fully confirm the validity of A2ARs as a new target for NPC1 treatment. As soon as new ligands with improved pharmacokinetic characteristics (i.e. orally active, with brain bioavailability and metabolic stability) will be obtained, A2AR agonists could represent a breakthrough in the treatment of NPC.

Original languageEnglish
Pages (from-to)1-11
Number of pages11
JournalNeurobiology of Disease
Volume110
DOIs
Publication statusPublished - Feb 2018

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Type C Niemann-Pick Disease
Adenosine
Sphingomyelins
Purkinje Cells
Rotarod Performance Test
Phenotype
Asymptomatic Diseases
Aptitude
Liver
Therapeutics
Intraperitoneal Injections
Posture
Drinking Water
Biological Availability
Weight Loss
Spleen
Pharmacokinetics
Cholesterol
Ligands
Calcium

Cite this

@article{94d02b90776449feb94b5a4b46096ab9,
title = "The adenosine Areceptor agonist T1-11 ameliorates neurovisceral symptoms and extends the lifespan of a mouse model of Niemann-Pick type C disease",
abstract = "Niemann-Pick C is a fatal neurovisceral disorder caused, in 95{\%} of cases, by mutation of NPC1 gene. Therapeutic options are extremely limited and new {"}druggable{"} targets are highly warranted. We previously demonstrated that the stimulation of the adenosine A2Areceptor (A2AR) normalized the pathological phenotype of cellular models of NPC1. Since the validation of A2ARs as a therapeutic target for NPC1 can be obtained only conducting studies in in vivo models of the disease, in the present paper, the effects of two agonists of A2ARs were evaluated in the mouse model Balb/c Npc1nih, hereafter indicated as NPC1-/-. The agonists CGS21680 (2.5 and 5mg/kg/day by intraperitoneal injection) and T1-11 (50mg/kg/day in drinking water) were administered at a presymptomatic stage of the disease of NPC1-/- mice (PN28 and PN30, respectively); the experimental groups were the following: vehicle-treated WT mice (N=16 for both CGS and T1-11 treatments); vehicle-treated NPC1-/- mice (N=14 for CGS and 12 for T1-11 treatment); CGS-treated NPC1-/- mice (N=7) and T1-11-treated NPC1-/- mice (N=11). The efficacy of the treatments was evaluated by comparing vehicle-treated and CGS or T1-11-treated NPC1-/- mice for their motor deficits (analyzed by both rotarod and footprint tests), hippocampal cognitive impairment (by Novel Object Recognition (NOR) test), cerebellar neurodegeneration (Purkinje neurons counting), and cholesterol and sphingomyelin accumulation in spleen and liver. Finally, the effect of both agonists on survival was evaluated by applying a humane late endpoint (weight loss >30{\%} of peak weight, punched posture and reduced activity in the cage). The results demonstrated that, while CGS21680 only slightly attenuated cognitive deficits, T1-11 ameliorated motor coordination, significantly improved cognitive impairments, increased the survival of Purkinje neurons and reduced sphingomyelin accumulation in the liver. More importantly, it significantly prolonged the lifespan of NPC1-/- mice. In vitro experiments conducted in a neuronal model of NPC1 demonstrated that the ability of T1-11 to normalize cell phenotype was mediated by the selective activation of A2ARs and modulation of intracellular calcium levels. In conclusion, our results fully confirm the validity of A2ARs as a new target for NPC1 treatment. As soon as new ligands with improved pharmacokinetic characteristics (i.e. orally active, with brain bioavailability and metabolic stability) will be obtained, A2AR agonists could represent a breakthrough in the treatment of NPC.",
author = "Antonella Ferrante and Antonella Pezzola and Andrea Matteucci and {Di Biase}, Antonella and Lucilla Attorri and Monica Armida and Alberto Martire and Yijuang Chern and Patrizia Popoli",
note = "Copyright {\circledC} 2017 Elsevier Inc. All rights reserved.",
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language = "English",
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TY - JOUR

T1 - The adenosine Areceptor agonist T1-11 ameliorates neurovisceral symptoms and extends the lifespan of a mouse model of Niemann-Pick type C disease

AU - Ferrante, Antonella

AU - Pezzola, Antonella

AU - Matteucci, Andrea

AU - Di Biase, Antonella

AU - Attorri, Lucilla

AU - Armida, Monica

AU - Martire, Alberto

AU - Chern, Yijuang

AU - Popoli, Patrizia

N1 - Copyright © 2017 Elsevier Inc. All rights reserved.

PY - 2018/2

Y1 - 2018/2

N2 - Niemann-Pick C is a fatal neurovisceral disorder caused, in 95% of cases, by mutation of NPC1 gene. Therapeutic options are extremely limited and new "druggable" targets are highly warranted. We previously demonstrated that the stimulation of the adenosine A2Areceptor (A2AR) normalized the pathological phenotype of cellular models of NPC1. Since the validation of A2ARs as a therapeutic target for NPC1 can be obtained only conducting studies in in vivo models of the disease, in the present paper, the effects of two agonists of A2ARs were evaluated in the mouse model Balb/c Npc1nih, hereafter indicated as NPC1-/-. The agonists CGS21680 (2.5 and 5mg/kg/day by intraperitoneal injection) and T1-11 (50mg/kg/day in drinking water) were administered at a presymptomatic stage of the disease of NPC1-/- mice (PN28 and PN30, respectively); the experimental groups were the following: vehicle-treated WT mice (N=16 for both CGS and T1-11 treatments); vehicle-treated NPC1-/- mice (N=14 for CGS and 12 for T1-11 treatment); CGS-treated NPC1-/- mice (N=7) and T1-11-treated NPC1-/- mice (N=11). The efficacy of the treatments was evaluated by comparing vehicle-treated and CGS or T1-11-treated NPC1-/- mice for their motor deficits (analyzed by both rotarod and footprint tests), hippocampal cognitive impairment (by Novel Object Recognition (NOR) test), cerebellar neurodegeneration (Purkinje neurons counting), and cholesterol and sphingomyelin accumulation in spleen and liver. Finally, the effect of both agonists on survival was evaluated by applying a humane late endpoint (weight loss >30% of peak weight, punched posture and reduced activity in the cage). The results demonstrated that, while CGS21680 only slightly attenuated cognitive deficits, T1-11 ameliorated motor coordination, significantly improved cognitive impairments, increased the survival of Purkinje neurons and reduced sphingomyelin accumulation in the liver. More importantly, it significantly prolonged the lifespan of NPC1-/- mice. In vitro experiments conducted in a neuronal model of NPC1 demonstrated that the ability of T1-11 to normalize cell phenotype was mediated by the selective activation of A2ARs and modulation of intracellular calcium levels. In conclusion, our results fully confirm the validity of A2ARs as a new target for NPC1 treatment. As soon as new ligands with improved pharmacokinetic characteristics (i.e. orally active, with brain bioavailability and metabolic stability) will be obtained, A2AR agonists could represent a breakthrough in the treatment of NPC.

AB - Niemann-Pick C is a fatal neurovisceral disorder caused, in 95% of cases, by mutation of NPC1 gene. Therapeutic options are extremely limited and new "druggable" targets are highly warranted. We previously demonstrated that the stimulation of the adenosine A2Areceptor (A2AR) normalized the pathological phenotype of cellular models of NPC1. Since the validation of A2ARs as a therapeutic target for NPC1 can be obtained only conducting studies in in vivo models of the disease, in the present paper, the effects of two agonists of A2ARs were evaluated in the mouse model Balb/c Npc1nih, hereafter indicated as NPC1-/-. The agonists CGS21680 (2.5 and 5mg/kg/day by intraperitoneal injection) and T1-11 (50mg/kg/day in drinking water) were administered at a presymptomatic stage of the disease of NPC1-/- mice (PN28 and PN30, respectively); the experimental groups were the following: vehicle-treated WT mice (N=16 for both CGS and T1-11 treatments); vehicle-treated NPC1-/- mice (N=14 for CGS and 12 for T1-11 treatment); CGS-treated NPC1-/- mice (N=7) and T1-11-treated NPC1-/- mice (N=11). The efficacy of the treatments was evaluated by comparing vehicle-treated and CGS or T1-11-treated NPC1-/- mice for their motor deficits (analyzed by both rotarod and footprint tests), hippocampal cognitive impairment (by Novel Object Recognition (NOR) test), cerebellar neurodegeneration (Purkinje neurons counting), and cholesterol and sphingomyelin accumulation in spleen and liver. Finally, the effect of both agonists on survival was evaluated by applying a humane late endpoint (weight loss >30% of peak weight, punched posture and reduced activity in the cage). The results demonstrated that, while CGS21680 only slightly attenuated cognitive deficits, T1-11 ameliorated motor coordination, significantly improved cognitive impairments, increased the survival of Purkinje neurons and reduced sphingomyelin accumulation in the liver. More importantly, it significantly prolonged the lifespan of NPC1-/- mice. In vitro experiments conducted in a neuronal model of NPC1 demonstrated that the ability of T1-11 to normalize cell phenotype was mediated by the selective activation of A2ARs and modulation of intracellular calcium levels. In conclusion, our results fully confirm the validity of A2ARs as a new target for NPC1 treatment. As soon as new ligands with improved pharmacokinetic characteristics (i.e. orally active, with brain bioavailability and metabolic stability) will be obtained, A2AR agonists could represent a breakthrough in the treatment of NPC.

U2 - 10.1016/j.nbd.2017.10.013

DO - 10.1016/j.nbd.2017.10.013

M3 - Article

C2 - 29079454

VL - 110

SP - 1

EP - 11

JO - Neurobiology of Disease

JF - Neurobiology of Disease

SN - 0969-9961

ER -