{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T20:42:56Z","timestamp":1789764176248,"version":"4.0.1"},"reference-count":60,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2016,11,23]],"date-time":"2016-11-23T00:00:00Z","timestamp":1479859200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"NIH National Institute of Neurological Disorders and Stroke","doi-asserted-by":"crossref","award":["1R21NS084392-01A1"],"award-info":[{"award-number":["1R21NS084392-01A1"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Batten Disease Support and Research Administration"},{"DOI":"10.13039\/100006518","name":"University of Nebraska Medical Center","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100006518","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2016,12]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Juvenile neuronal ceroid lipofuscinosis (JNCL), or juvenile Batten disease, is a pediatric lysosomal storage disease caused by autosomal recessive mutations in <jats:italic>CLN3<\/jats:italic>, 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\u20104 (PDE4) inhibitors (rolipram, roflumilast, and PF\u201006266047) could mitigate behavioral deficits and cell\u2010specific pathology in the Cln3<jats:sup>\u0394ex7\/8<\/jats:sup> mouse model of JNCL.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In a randomized, blinded study, wild\u2010type (WT) and Cln3<jats:sup>\u0394ex7\/8<\/jats:sup> 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\u2010associated membrane protein 1), and astrocyte glutamate transporter expression (glutamate\/aspartate transporter) were also examined in WT and Cln3<jats:sup>\u0394ex7\/8<\/jats:sup> animals.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>cAMP levels were significantly reduced in the Cln3<jats:sup>\u0394ex7\/8<\/jats:sup> brain, and were restored by PF\u201006266047. PDE4 inhibitors significantly improved motor function in Cln3<jats:sup>\u0394ex7\/8<\/jats:sup> 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>These studies reveal neuroprotective effects for PDE4 inhibitors in Cln3<jats:sup>\u0394ex7\/8<\/jats:sup> mice and support their therapeutic potential in JNCL patients. Ann Neurol 2016;80:909\u2013923<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.24815","type":"journal-article","created":{"date-parts":[[2016,11,23]],"date-time":"2016-11-23T10:14:49Z","timestamp":1479896089000},"page":"909-923","source":"Crossref","is-referenced-by-count":36,"title":["Efficacy of phosphodiesterase\u20104 inhibitors in juvenile Batten disease (CLN3)"],"prefix":"10.1002","volume":"80","author":[{"given":"Amy","family":"Aldrich","sequence":"first","affiliation":[{"name":"Department of Pathology and Microbiology University of Nebraska Medical Center Omaha NE"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan E.","family":"Bosch","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Experimental Neuroscience University of Nebraska Medical Center Omaha NE"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Fallet","sequence":"additional","affiliation":[{"name":"Department of Pathology and Microbiology 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