- Comment
- Published:
- Fernando E. Padovan-Neto ORCID: orcid.org/0000-0002-5529-31681,
- Ana Júlia de Oliveira Cerveira1,
- Aline da Silva1 &
- …
- Danilo Leandro Ribeiro1
Neuropsychopharmacology (2024)Cite this article
-
22 Accesses
-
Metrics details
Subjects
- Pharmacology
- Psychiatric disorders
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 circuitryassociated 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 your institution
Access options
Change institution
Buy or subscribe
Subscribe to this journal
Receive 13 print issues and online access
251,40€ per year
only 19,34 € per issue
Learn more
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
References
Lord C, Charman T, Havdahl A, Carbone P, Anagnostou E, Boyd B, et al. The Lancet Commission on the future of care and clinical research in autism. Lancet. 2022;399:271–334.
Bondarev AD, Attwood MM, Jonsson J, Chubarev VN, Tarasov VV, Liu W, et al. Recent developments of phosphodiesterase inhibitors: Clinical trials, emerging indications and novel molecules. Front Pharm. 2022;13:1057083.
Bender AT, Beavo JA. Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharm Rev. 2006;58:488–520.
Delhaye S, Bardoni B. Role of phosphodiesterases in the pathophysiology of neurodevelopmental disorders. Mol Psychiatry. 2021;26:4570–82.
Hendouei F, Sanjari Moghaddam H, Mohammadi MR, Taslimi N, Rezaei F, Akhondzadeh S. Resveratrol as adjunctive therapy in treatment of irritability in children with autism: A double-blind and placebo-controlled randomized trial. J Clin Pharm Ther. 2020;45:324–34.
Ebrahimi P, Seyedmirzaei H, Moradi K, Bagheri S, Moeini M, Mohammadi MR, et al. Cilostazol as adjunctive therapy in treatment of children with autism spectrum disorders: a double-blind and placebo-controlled randomized trial. Int Clin Psychopharmacol. 2023;38:89–95.
Berry-Kravis EM, Harnett MD, Reines SA, Reese MA, Ethridge LE, Outterson AH, et al. Inhibition of phosphodiesterase-4D in adults with fragile X syndrome: a randomized, placebo-controlled, phase 2 clinical trial. Nat Med. 2021;27:862–70.
Lakics V, Karran EH, Boess FG. Quantitative comparison of phosphodiesterase mRNA distribution in human brain and peripheral tissues. Neuropharmacology. 2010;59:367–74.
Chmielewski WX, Beste C. Action control processes in autism spectrum disorder – Insights from a neurobiological and neuroanatomical perspective. Prog Neurobiol. 2015;124:49–83.
Chang J, Gilman SR, Chiang AH, Sanders SJ, Vitkup D. Genotype to phenotype relationships in autism spectrum disorders. Nat Neurosci. 2014;18:191–8.
Nickl-Jockschat T, Habel U, Maria Michel T, Manning J, Laird AR, Fox PT, et al. Brain structure anomalies in autism spectrum disorder-a meta-analysis of VBM studies using anatomic likelihood estimation. Hum Brain Mapp. 2012;33:1470–89.
Fuccillo MV. Striatal circuits as a common node for autism pathophysiology. Front Neurosci. 2016;10:159489.
Cheng Y, Wang ZM, Tan W, Wang X, Li Y, Bai B, et al. Partial loss of psychiatric risk gene Mir137 in mice causes repetitive behavior and impairs sociability and learning via increased Pde10a. Nat Neurosci. 2018;21:1689–703.
De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Cicek AE, et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature. 2014;515:209–15.
Luhach K, Kulkarni GT, Singh VP, Sharma B. Vinpocetine amended prenatal valproic acid induced features of ASD possibly by altering markers of neuronal function, inflammation, and oxidative stress. Autism Res. 2021;14:2270–86.
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 in PubMedGoogle Scholar
- Ana Júlia de Oliveira Cerveira
View author publications
You can also search for this author in PubMedGoogle Scholar
- Aline da Silva
View author publications
You can also search for this author in PubMedGoogle Scholar
- Danilo Leandro Ribeiro
View author publications
You can also search for this author in PubMedGoogle 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
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. (2024). https://doi.org/10.1038/s41386-024-01860-z
Received:
Revised:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41386-024-01860-z