Treatment of the Ppt1^–/– Mouse Model of Infantile Neuronal Ceroid Lipofuscinosis With the N-methyl-d-aspartate (NMDA) Receptor Antagonist Memantine

Abstract

The neuronal ceroid lipofuscinoses, a family of neurodegenerative lysosomal storage disorders, represent the most common cause of pediatric-onset neurodegeneration. The infantile form has a devastatingly early onset and one of the fastest progressing disease courses. Despite decades of research, the molecular mechanisms driving neuronal loss in infantile neuronal ceroid lipofuscinosis remain unknown. We have previously shown that NMDA-type glutamate receptors in the Ppt1−/− mouse model of this disease exhibit a hyperfunctional phenotype and postulate that aberrant glutamatergic activity may contribute to neural pathology in both the mouse model and human patients. To test this hypothesis, we treated Ppt1−/− mice with the NMDA receptor antagonist memantine and assessed their response to the drug using an accelerating rotarod. At 20 mg/kg, memantine treatment induced a delayed but notable improvement in Ppt1−/− mice. Much remains to be assessed before moving to patient trials, but these results suggest memantine has potential as a treatment.

Pre-clinical Mouse Models of Neurodegenerative Lysosomal Storage Diseases

“…Akin to other neurodegenerative diseases such as Alzheimer's disease and Huntington's disease, LSDs can elicit aberrant neuronal signaling leading to neurotransmitter mediated excitotoxicity. Pre-clinical trials evaluating receptor antagonism (RA), AMPA-RA (Kovacs and Pearce, 2008) and NMDA-RA (Finn et al, 2013) have improved the neurobehavioral phenotypes associated with LSDs. Furthermore, a number of pharmacological agents have been explored eliciting various effects from modulating membrane fluidity (Schultz et al, 2018), modulating Ca 2+ (Chang et al, 2007) or cholesterol levels (Erickson et al, 2000;Pelled et al, 2003;Kim et al, 2007;Repa et al, 2007;Abi-Mosleh et al, 2009;Liu et al, 2010;Taylor et al, 2012;Hovakimyan et al, 2013;Nusca et al, 2014;Tanaka et al, 2014;Soga et al, 2015;Demais et al, 2016;Liou et al, 2016), and enhancing enzyme activity (Arroyo et al, 2014) via the use of neurosteroids (NS) (Griffin et al, 2004;Liao et al, 2009).…”

“…Ppt1 (−/−) (Gupta et al, 2001) Macauley et al, 2014;Shyng et al, 2017), AO (Wei et al, 2011;Saha et al, 2012), ERT (Hu et al, 2012), NMDARA (Finn et al, 2013), SRT (Sarkar et al, 2013) Ppt1 ( Represents murine models that display a similar yet milder disease progression than human patients. *The neuronal degeneration and recaps clinical phenotype designations for the Mgat3 (CKO) model were interpreted from the conditional knockout mice model crossed to with CMV-Cre line; a model with ubiquitous expression across all tissue types.…”

Homozygous PPT1 Splice Donor Mutation in a Cane Corso Dog With Neuronal Ceroid Lipofuscinosis

“…At least 4 different transgenic mouse models carrying nullifying Ppt1 mutations have been created and shown to exhibit CLN1‐like disease characteristics . These models are the subjects of ongoing and planned evaluations of therapeutic interventions intended for human CLN1 patients . Due to differences in longevity, size, and the complexities of neuroanatomy and behavior, canine NCL models have some advantages over rodent models for optimizing therapeutic interventions or establishing their efficacy.…”

“…[15][16][17][18] These models are the subjects of ongoing and planned evaluations of therapeutic interventions intended for human CLN1 patients. [19][20][21][22][23][24] Due to differences in longevity, size, and the complexities of neuroanatomy and behavior, canine NCL models have some advantages over rodent models for optimizing therapeutic interventions or establishing their efficacy. Indeed, a TPP1-deficient canine model for the CLN2 form of NCL has been used to develop enzyme replacement treatment 25 and paved the way for ongoing human trials (https://clinical trials.gov/ct2/show/NCT02678689).…”

Progress in the Development of Small Molecule Therapeutics for the Treatment of Neuronal Ceroid Lipofuscinoses (NCLs)

“…The authors conclude that further tests are required but memantine may be useful in INCL patients who have already developed disease symptoms. 70 …”