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Access through your institution Buy or subscribe Autism spectrum disorder (ASD) encompasses a range of neurodevelopmental conditions characterized by differences in social communication and

interaction, coupled with repetitive behaviors and interests. Its features vary widely, from speech and language delays to sensory hypo- or hypersensitivity and stereotypic behaviors that

can include aggression or self-harm. These often coincide with psychiatric and medical co-occurring conditions such as attention-deficit/hyperactivity disorder, anxiety, and irritability.

Current psychopharmacological treatments, including atypical antipsychotics, serotonergic agents, alpha-2 agonists, and psychostimulants, primarily address these associated symptoms. While

useful, these medications frequently require polypharmacy, posing challenges due to potential drug interactions and side effects. Despite progress in understanding the brain circuitry 

associated with ASD [1], effective diagnostic biomarkers or treatments for its core symptoms remain elusive. Interest in cyclic nucleotide phosphodiesterase (PDE) inhibitors has grown.

Approved indications for PDE inhibitors include respiratory, cardiovascular, inflammatory, and nervous system disorders [2]. PDE5 inhibitors such as sildenafil, vardenafil, avanafil, and

tadalafil have been used as therapeutic options for individuals with erectile dysfunction. Cyclic nucleotides cAMP (3′,5′-cyclic adenosine monophosphate) and cGMP (3′,5′-cyclic guanosine

monophosphate) act as crucial second messengers in the brain, transforming neuromodulatory signals into functional responses that modulate neuronal activity. Their intracellular

concentrations are regulated by PDE enzymes, which are categorized into 11 families. Each family’s affinity for cyclic nucleotides varies; PDEs 1, 2, 3, 10, and 11 target both cAMP and cGMP,

whereas PDEs 4, 7, and 8 are cAMP-specific, and PDEs 5, 6, and 9 are cGMP-specific. These families comprise multiple genes, yielding over 100 human isoforms and splice variants [3]. While

preclinical studies suggest that modulating PDE activity could benefit ASD [4], clinical trials for autistic individuals remain limited. This is a preview of subscription content, access via

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Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support REFERENCES * Lord C, Charman T, Havdahl A, Carbone P, Anagnostou E, Boyd B, et al. The Lancet

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  PubMed  Google Scholar  Download references FUNDING The authors were funded by the grants #2019/04188-0 (DLR), and #2017/00003-0 (FEP-N) from the São Paulo Research Foundation (FAPESP) and

grant # 312009/2022-4 (FEP-N) from the National Council for Scientific and Technological Development (CNPq). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Psychology, Faculty

of Philosophy, Sciences and Letters of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil Fernando E. Padovan-Neto, Ana Júlia de Oliveira Cerveira, Aline da Silva & 

Danilo Leandro Ribeiro Authors * Fernando E. Padovan-Neto View author publications You can also search for this author inPubMed Google Scholar * Ana Júlia de Oliveira Cerveira View author

publications You can also search for this author inPubMed Google Scholar * Aline da Silva View author publications You can also search for this author inPubMed Google Scholar * Danilo

Leandro Ribeiro View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS FEP-N: Conceptualization, literature review, writing- original draft

preparation, writing- reviewing and editing. AJOC, AS, and DLR: Literature review, writing- original draft preparation. CORRESPONDING AUTHOR Correspondence to Fernando E. Padovan-Neto.

ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing interests. ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer Nature remains neutral with regard to jurisdictional

claims in published maps and institutional affiliations. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Padovan-Neto, F.E., Cerveira, A.J.d.O., da

Silva, A. _et al._ Beyond traditional pharmacology: evaluating phosphodiesterase inhibitors in autism spectrum disorder. _Neuropsychopharmacol._ 49, 1359–1360 (2024).

https://doi.org/10.1038/s41386-024-01860-z Download citation * Received: 29 December 2023 * Revised: 01 April 2024 * Accepted: 01 April 2024 * Published: 11 April 2024 * Issue Date: August

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