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 L Kielian

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Objective: 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 Cln3Δex7/8 mouse model of JNCL. Methods: In a randomized, blinded study, wild-type (WT) and Cln3Δex7/8 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 Cln3Δex7/8 animals. Results: cAMP levels were significantly reduced in the Cln3Δex7/8 brain, and were restored by PF-06266047. PDE4 inhibitors significantly improved motor function in Cln3Δex7/8 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. Interpretation: These studies reveal neuroprotective effects for PDE4 inhibitors in Cln3Δex7/8 mice and support their therapeutic potential in JNCL patients. Ann Neurol 2016;80:909–923.

Original languageEnglish (US)
Pages (from-to)909-923
Number of pages15
JournalAnnals of Neurology
Volume80
Issue number6
DOIs
StatePublished - Dec 1 2016

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Phosphodiesterase 4 Inhibitors
Neuronal Ceroid-Lipofuscinoses
Amino Acid Transport System X-AG
Cyclic AMP
Pathology
Astrocytes
Lysosomal-Associated Membrane Protein 1
Rolipram
Lysosomal Storage Diseases
Premature Mortality
Wild Animals
Glial Fibrillary Acidic Protein
Second Messenger Systems
Neuroprotective Agents
Blindness
Neuroglia
Disease Progression
Seizures
Quality of Life
Pediatrics

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Aldrich, A., Bosch, M. E., Fallet, R., Odvody, J., Burkovetskaya, M., Rama Rao, K. V., ... Kielian, T. L. (2016). Efficacy of phosphodiesterase-4 inhibitors in juvenile Batten disease (CLN3). Annals of Neurology, 80(6), 909-923. https://doi.org/10.1002/ana.24815

Efficacy of phosphodiesterase-4 inhibitors in juvenile Batten disease (CLN3). / Aldrich, Amy; Bosch, Megan E.; Fallet, Rachel; Odvody, Jessica; Burkovetskaya, Maria; Rama Rao, Kakulavarapu V.; Cooper, Jonathan D.; Drack, Arlene V.; Kielian, Tammy L.

In: Annals of Neurology, Vol. 80, No. 6, 01.12.2016, p. 909-923.

Research output: Contribution to journalArticle

Aldrich, A, Bosch, ME, Fallet, R, Odvody, J, Burkovetskaya, M, Rama Rao, KV, Cooper, JD, Drack, AV & Kielian, TL 2016, 'Efficacy of phosphodiesterase-4 inhibitors in juvenile Batten disease (CLN3)', Annals of Neurology, vol. 80, no. 6, pp. 909-923. https://doi.org/10.1002/ana.24815
Aldrich A, Bosch ME, Fallet R, Odvody J, Burkovetskaya M, Rama Rao KV et al. Efficacy of phosphodiesterase-4 inhibitors in juvenile Batten disease (CLN3). Annals of Neurology. 2016 Dec 1;80(6):909-923. https://doi.org/10.1002/ana.24815
Aldrich, Amy ; Bosch, Megan E. ; Fallet, Rachel ; Odvody, Jessica ; Burkovetskaya, Maria ; Rama Rao, Kakulavarapu V. ; Cooper, Jonathan D. ; Drack, Arlene V. ; Kielian, Tammy L. / Efficacy of phosphodiesterase-4 inhibitors in juvenile Batten disease (CLN3). In: Annals of Neurology. 2016 ; Vol. 80, No. 6. pp. 909-923.
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