Effects of a novel phosphodiesterase 10A inhibitor in non-human primates: A therapeutic approach for schizophrenia with improved side effect profile

Abstract

Schizophrenia symptoms are associated with alterations in basal ganglia-cortical networks that include the cyclic nucleotides (cAMP/cGMP) signaling pathways. Phosphodiesterase 10A (PDE10A) inhibitors have been considered as therapeutic agents for schizophrenia because the regulation of cAMP and cGMP in the striatum by PDE10A plays an important role in the signaling mechanisms of the striatal-cortical network, and thereby in cognitive function. In the present study we assessed in non-human primates (NHPs) the effects of a novel PDE10A inhibitor (FRM-6308) that has demonstrated high potency and selectivity for human recombinant PDE10A in vitro. The behavioral effects of FRM-6308 in a dose range were determined in rhesus monkeys using a standardized motor disability scale for primates, motor tasks, and the “drug effects on the nervous system” (DENS) scale. The neuronal metabolic effects of FRM-6308 were determined with [(18)F]-fluorodeoxyglucose PET imaging. Results showed that FRM-6308 did not have any specific effects on the motor system at s.c. doses up to 0.32 mg/kg in NHPs, which induced a significant increase in the FDG-SUV in striatum (F 16.069, p < 0.05) and cortical (F 15.181, p < 0.05) regions. Higher doses induced sedation and occasional involuntary movements with clear development of tolerance after repeated exposures. These findings suggest that FRM-6308 has the adequate pharmacological profile to advance testing in clinical trials and demonstrate antipsychotic efficacy of PDE10A inhibition for the treatment of schizophrenia patients.

Effect of Peony‐Glycyrrhiza Decoction on Amisulpride‐Induced Hyperprolactinemia in Women with Schizophrenia: A Preliminary Study

“…However, the long-term use of antipsychotic medications may lead to a large quantity of adverse reactions, such as the extrapyramidal reaction in the nervous system, leucopenia in the blood system, and Prolactin (PRL) and metabolic disorders in the endocrine system. It will affect the patient's physical health, treatment compliance, and therapeutic effect greatly [ 3 ]. If the adverse reactions could not be controlled in time, the patient may have to face the dilemma of drug withdrawal, which subsequently results in disease recurrence [ 4 ].…”

A Selective Phosphodiesterase 10A Inhibitor Reduces L‐Dopa‐Induced Dyskinesias in Parkinsonian Monkeys

“…This scale rates rapid changes in cortical (attentiveness and reactivity), motor (eye movement and involuntary movements), and autonomic functions (salivation, upper and lower gastrointestinal functions, and urinary function) after acute drug administration. The Klüver board test (KBT) was also used to assess hand movement speed and fine motor skills . In all trials, motor behavior in the off state (parkinsonian motor disability) was scored just before administration of MR1916 (or amantadine) followed by administration of l ‐dopa (subcutaneous or oral).…”

“…The Kl€ uver board test (KBT) was also used to assess hand movement speed and fine motor skills. 34 In all trials, motor behavior in the off state (parkinsonian motor disability) was scored just before administration of MR1916 (or amantadine) followed by administration of L-dopa (subcutaneous or oral). After L-dopa administration, scores were taken starting at 30 minutes postinjection, and continuing every 20-minute interval during the duration of the motor response induced by L-dopa (on state).…”

Sexually dimorphic responses to MPTP found in microglia, inflammation and gut microbiota in a progressive monkey model of Parkinson’s disease

“…accounting for body mass and injected activity of the tracer (Zhang et al, 2012). SUV allows precise assessment of activity changes in response to drug treatments (Masilamoni et al, 2016;Zhang et al, 2012). No reference brain region was used to assess background activity because systemic MPTP administration is likely to affect all regions of the brain, albeit differentially.…”