ABSTRACT
Schizophrenia is a severe mental disorder that affects more than 1% of the population worldwide. Dopamine system dysfunction and alterations in glutamatergic neurotransmission are strongly implicated in the aetiology of schizophrenia. To date, antipsychotic drugs are the only available treatment for the symptoms of schizophrenia. These medications, which act as D2-receptor antagonist, adequately address the positive symptoms of the disease, but they fail to improve the negative symptoms and cognitive impairment. In schizophrenia, cognitive impairment is a core feature of the disorder. Therefore, the treatment of cognitive impairment and the other symptoms related to schizophrenia remains a significant unmet medical need. Currently, phosphodiesterases (PDEs) are considered the best drug target for the treatment of schizophrenia since many PDE subfamilies are abundant in the brain regions that are relevant to cognition. Thus, this review aims to illustrate the mechanism of PDEs in treating the symptoms of schizophrenia and summarises the encouraging results of PDE inhibitors as anti-schizophrenic drugs in preclinical and clinical studies.
Subject(s)
Antipsychotic Agents/chemistry , Cognition Disorders/drug therapy , Cognition/drug effects , Nootropic Agents/chemistry , Phosphodiesterase Inhibitors/chemistry , Phosphoric Diester Hydrolases/metabolism , Schizophrenia/drug therapy , Antipsychotic Agents/pharmacology , Brain , Dopamine/metabolism , Excitatory Amino Acid Agents/chemistry , Excitatory Amino Acid Agents/pharmacology , Humans , Molecular Targeted Therapy , Nootropic Agents/pharmacology , Phosphodiesterase Inhibitors/pharmacology , Signal Transduction , Structure-Activity Relationship , Synaptic Transmission/drug effectsABSTRACT
BACKGROUND: Phosphodiesterases (PDEs) are enzymes that play a key role in terminating cyclic nucleotides signalling by catalysing the hydrolysis of 3', 5'- cyclic adenosine monophosphate (cAMP) and/or 3', 5' cyclic guanosine monophosphate (cGMP), the second messengers within the cell that transport the signals produced by extracellular signalling molecules which are unable to get into the cells. However, PDEs are proteins which do not operate alone but in complexes that made up of a many proteins. OBJECTIVE: This review highlights some of the general characteristics of PDEs and focuses mainly on the Protein-Protein Interactions (PPIs) of selected PDE enzymes. The objective is to review the role of PPIs in the specific mechanism for activation and thereby regulation of certain biological functions of PDEs. METHODS: The article discusses some of the PPIs of selected PDEs as reported in recent scientific literature. These interactions are critical for understanding the biological role of the target PDE. RESULTS: The PPIs have shown that each PDE has a specific mechanism for activation and thereby regulation a certain biological function. CONCLUSION: Targeting of PDEs to specific regions of the cell is based on the interaction with other proteins where each PDE enzyme binds with specific protein(s) via PPIs.
