Efficacy of phosphodiesterase-4 inhibitors in juvenile Batten disease (CLN3)

Amy Aldrich; Megan E Bosch; Rachel Fallet; Jessica Odvody; Maria Burkovetskaya; Kakulavarapu V Rama Rao; Jonathan D Cooper; Arlene V Drack; Tammy Kielian

doi:10.1002/ana.24815

Back

Efficacy of phosphodiesterase-4 inhibitors in juvenile Batten disease (CLN3)

Journal article

Open access

Peer reviewed

Efficacy of phosphodiesterase-4 inhibitors in juvenile Batten disease (CLN3)

Amy Aldrich, Megan E Bosch, Rachel Fallet, Jessica Odvody, Maria Burkovetskaya, Kakulavarapu V Rama Rao, Jonathan D Cooper, Arlene V Drack and Tammy Kielian

Annals of neurology, Vol.80(6), pp.909-923

12/2016

DOI: 10.1002/ana.24815

PMCID: PMC5215570

PMID: 27804148

Files and links (1)

url

https://doi.org/10.1002/ana.24815View

Published (Version of record) Open Access

Abstract

Juvenile neuronal ceroid lipofuscinosis (JNCL), or juvenile Batten disease, is a pediatric lysosomal storage disease caused by autosomal recessive mutations in CLN3, typified by blindness, seizures, progressive cognitive and motor decline, and premature death. Currently, there is no treatment for JNCL that slows disease progression, which highlights the need to explore novel strategies to extend the survival and quality of life of afflicted children. Cyclic adenosine monophosphate (cAMP) is a second messenger with pleiotropic effects, including regulating neuroinflammation and neuronal survival. Here we investigated whether 3 phosphodiesterase-4 (PDE4) inhibitors (rolipram, roflumilast, and PF-06266047) could mitigate behavioral deficits and cell-specific pathology in the Cln3 mouse model of JNCL. In a randomized, blinded study, wild-type (WT) and Cln3 mice received PDE4 inhibitors daily beginning at 1 or 3 months of age and continuing for 6 to 9 months, with motor deficits assessed by accelerating rotarod testing. The effect of PDE4 inhibitors on cAMP levels, astrocyte and microglial activation (glial fibrillary acidic protein and CD68, respectively), lysosomal pathology (lysosomal-associated membrane protein 1), and astrocyte glutamate transporter expression (glutamate/aspartate transporter) were also examined in WT and Cln3 animals. cAMP levels were significantly reduced in the Cln3 brain, and were restored by PF-06266047. PDE4 inhibitors significantly improved motor function in Cln3 mice, attenuated glial activation and lysosomal pathology, and restored glutamate transporter expression to levels observed in WT animals, with no evidence of toxicity as revealed by blood chemistry analysis. These studies reveal neuroprotective effects for PDE4 inhibitors in Cln3 mice and support their therapeutic potential in JNCL patients. Ann Neurol 2016;80:909-923.

Motor Skills - drug effects

Male

Glial Fibrillary Acidic Protein - metabolism

Rolipram - therapeutic use

Antigens, CD - metabolism

Brain - metabolism

Cyclopropanes - therapeutic use

Benzamides - therapeutic use

Neuronal Ceroid-Lipofuscinoses - genetics

Neuroprotective Agents - pharmacology

Aminopyridines - therapeutic use

Amino Acid Transport System X-AG - biosynthesis

Cyclic AMP - metabolism

Disease Models, Animal

Neuronal Ceroid-Lipofuscinoses - drug therapy

Molecular Chaperones - genetics

Phosphodiesterase 4 Inhibitors - therapeutic use

Phosphodiesterase 4 Inhibitors - pharmacology

Gene Knock-In Techniques

Membrane Glycoproteins - genetics

Brain - drug effects

Rotarod Performance Test

Animals

Antigens, Differentiation, Myelomonocytic - metabolism

Lysosomal-Associated Membrane Protein 1 - metabolism

Mice

Details

Title: Subtitle: Efficacy of phosphodiesterase-4 inhibitors in juvenile Batten disease (CLN3)
Creators: Amy Aldrich - Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE
Megan E Bosch - Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE
Rachel Fallet - Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE
Jessica Odvody - Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE
Maria Burkovetskaya - Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE
Kakulavarapu V Rama Rao - Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE
Jonathan D Cooper - Los Angeles Biomedical Research Institute and David Geffen School of Medicine at UCLA, Harbor UCLA Medical Center, Torrance, CA
Arlene V Drack - Department of Ophthalmology and Visual Sciences, University of Iowa Carver College of Medicine, Iowa City, IA
Tammy Kielian - Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE
Resource Type: Journal article
Publication Details: Annals of neurology, Vol.80(6), pp.909-923
DOI: 10.1002/ana.24815
PMID: 27804148
PMCID: PMC5215570
NLM abbreviation: Ann Neurol
ISSN: 0364-5134
eISSN: 1531-8249
Publisher: United States
Grant note: R21 NS084392 / NINDS NIH HHS
Language: English
Date published: 12/2016
Academic Unit: Stead Family Department of Pediatrics; Ophthalmology and Visual Sciences
Record Identifier: 9983980054902771

Metrics

20 Record Views

34 Times Cited - Web of Science