The Phosphodiesterase 10A Inhibitor PF-2545920 Enhances Hippocampal Excitability and Seizure Activity Involving the Upregulation of GluA1 and NR2A in Post-synaptic Densities

Abstract

Phosphodiesterase regulates the homeostasis of cAMP and cGMP, which increase the strength of excitatory neural circuits and/or decrease inhibitory synaptic plasticity. Abnormally, synchronized synaptic transmission in the brain leads to seizures. A phosphodiesterase 10A (PDE10A) inhibitor PF-2545920 has recently attracted attention as a potential therapy for neurological and psychiatric disorders. We hypothesized that PF-2545920 plays an important role in status epilepticus (SE) and investigated the underlying mechanisms. PDE10A was primarily located in neurons, and PDE10A expression increased significantly in patients with temporal lobe epilepsy. PF-2545920 enhanced the hyperexcitability of pyramidal neurons in rat CA1, as measured by the frequency of action potentials and miniature excitatory post-synaptic current. GluA1 and NR2A expression also increased significantly in post-synaptic densities, with or without SE in rats treated with PF-2545920. The ratio of p-GluA1/GluA1 increased in the presence of PF-2545920 in groups with SE. Our results suggest that PF-2545920 facilitates seizure activity via the intracellular redistribution of GluA1 and NR2A in the hippocampus. The upregulation of p-GluA1 may play an important role in trafficking GluA1 to post-synaptic densities. The data suggest it would be detrimental to use the drug in seizure patients and might cause neuronal hyperexcitability in non-epileptic individuals.

Genome-Wide Association of Genetic Variants With Refraction, Axial Length, and Corneal Curvature: A Longitudinal Study of Chinese Schoolchildren

“…PDE10A is mostly expressed in the retina (Wagner et al, 2013) and is involved in circadian rhythm, and the levels of the PDE10A protein display circadian rhythm at retinal photoreceptors (Wolloscheck et al, 2011), suggesting potential roles of this protein in the visual circle. PDE10A has gained attention as a therapeutic target for psychiatric disorders (Wilson and Brandon, 2015;Zhang et al, 2017;Cheng et al, 2018). Few studies have reported an association between PDE10A and myopia, and no prior study has analyzed the relationship between PDE10A and ocular parameters.…”

Spatiotemporal Expression of SphK1 and S1PR2 in the Hippocampus of Pilocarpine Rat Model and the Epileptic Foci of Temporal Lobe Epilepsy

“…Two stainless steel screws were implanted as reference electrodes into focal lobe skulls using dental cement. The recording electrodes were implanted into the right dorsal hippocampus (2.8 mm lateral and 3.6 mm posterior to bregma) with a depth of 3.6 mm underneath the dura mater ( Budantsev et al, 1993 ; Zhang et al, 2017 ). The local field potentials (LFPs) were recorded using a multichannel acquisition processor system (Plexon, Dallas, TX, United States).…”

“…These TLE patients experienced three or more seizures per month. Control study used histologically normal temporal cortex from ten patients treated for severe intracranial hypertension after traumatic brain injury ( Zhang et al, 2017 ; Lu et al, 2019 ). These patients had no seizures after trauma, no history of epilepsy, no exposure to anti-epilepsy drugs or other neurological diseases.…”

The CB2 Receptor as a Novel Therapeutic Target for Epilepsy Treatment

“…Negative allosteric modulation of CB 2 R activity by CBD might interpret its action for antiseizure and other neural disorders, which provides us with novel insights to develop its medical application [74]. Regarding CB 2 R, CBD-DMH, a modification on different pharmacophoric sties, was considered to promote a conformational change in CB 2 R, which favors G protein-dependent signaling rather than β-arrestin-dependent signaling [75]. However, there are very few modulators of CB 1 R and CB 2 R reported in the literature.…”

“…When seizures occur, levels of cAMP increase in the brain. The appearance of cAMP signaling can be divided into temporary influence on neuronal excitability, including ion channel or receptor phosphorylation [75], and long-term effects on epileptogenesis, such as effects regulated by cAMP response factor binding protein, CREB [94]. By coupling to G i proteins, the activation of CB 2 Rs causes inhibition of AC activity and downregulation of cAMP release [95].…”