Miglustat Reverts the Impairment of Synaptic Plasticity in a Mouse Model of NPC Disease.

G D’Arcangelo,D Grossi,A Cutarelli,A Zaratti,C Frank,S Rufini,D Merlo,A Cardinale,M Racaniello,V Tancredi

doi:10.1155/2016/3830424

Abstract

Niemann-Pick type C disease is an autosomal recessive storage disorder, characterized by abnormal sequestration of unesterified cholesterol within the late endolysosomal compartment of cells and accumulation of gangliosides and other sphingolipids. Progressive neurological deterioration and insurgence of symptoms like ataxia, seizure, and cognitive decline until severe dementia are pathognomonic features of the disease. Here, we studied synaptic plasticity phenomena and evaluated ERKs activation in the hippocampus of BALB/c NPC1−/− mice, a well described animal model of the disease. Our results demonstrated an impairment of both induction and maintenance of long term synaptic potentiation in NPC1−/− mouse slices, associated with the lack of ERKs phosphorylation. We then investigated the effects of Miglustat, a recent approved drug for the treatment of NPCD. We found that in vivo Miglustat administration in NPC1−/− mice was able to rescue synaptic plasticity deficits, to restore ERKs activation and to counteract hyperexcitability. Overall, these data indicate that Miglustat may be effective for treating the neurological deficits associated with NPCD, such as seizures and dementia.

Highlights

Niemann-Pick type C disease (NPCD) is a panethnic, fatal, autosomal recessive, neurovisceral lipid storage disorder with infantile and juvenile onset in 95% of cases and adult onset in 5% of cases [1]
We demonstrated that basal synaptic transmission (BST) recorded in the CA1 region of hippocampal slices from NPC1−/− mice was enhanced with respect to slices from Wild Type (WT) mice [15]
In slices from NPC1−/− mice treated with saline solution (n = 5 from 5 different animals), the population spikes (PSs) values did not vary with respect to the untreated (129.4 ± 7.2 versus 127.1 ± 6 at 20 min; 147.2 ± 11.2 versus 144 ± 10.8 at 60 min)

Summary

Introduction

Niemann-Pick type C disease (NPCD) is a panethnic, fatal, autosomal recessive, neurovisceral lipid storage disorder with infantile and juvenile onset in 95% of cases and adult onset in 5% of cases [1]. Mutations in NPC1 and NPC2 give rise to severe abnormalities in the functioning of this transport system with excess storage of lipids as cholesterol, glycosphingolipids, and sphingosine in the late endosomal and lysosomal intracellular compartments, associated with peripheral and central organ dysfunction [2]. Nbutyldeoxynojirimycin (Miglustat; Zavesca, Actelion Pharmaceuticals), a drug initially used for the treatment of several dyslipidosis including GM1 gangliosidosis, Gaucher type I, and Tay-Sachs disease, has been approved in 2009 for the treatment of progressive neurological manifestations in adult and pediatric patients affected by NPCD [4,5,6,7]. Undeniable advantages concerning some neurological symptoms have been noticed in clinic, the reason why cells presenting

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