The IUPHAR/BPS Guide to PHARMACOLOGY in 2018: updates and expansion to encompass the new guide to IMMUNOPHARMACOLOGY

Background and PurposeA non‐psychoactive phytocannabinoid, cannabidiol (CBD), shows promising results as an effective potential antiepileptic drug in some forms of refractory epilepsy. To elucidate the mechanisms by which CBD exerts its anti‐seizure effects, we investigated its effects at synaptic connections and on the intrinsic membrane properties of hippocampal CA1 pyramidal cells and two major inhibitory interneurons: fast spiking, parvalbumin (PV)‐expressing and adapting, cholecystokinin (CCK)‐expressing interneurons. We also investigated whether in vivo treatment with CBD altered the fate of CCK and PV interneurons using immunohistochemistry.Experimental ApproachElectrophysiological intracellular whole‐cell recordings combined with neuroanatomy were performed in acute brain slices of rat temporal lobe epilepsy in in vivo (induced by kainic acid) and in vitro (induced by Mg2+‐free solution) epileptic seizure models. For immunohistochemistry experiments, CBD was administered in vivo (100 mg·kg−1) at zero time and 90 min post status epilepticus, induced with kainic acid.Key ResultsBath application of CBD (10 μM) dampened excitability at unitary synapses between pyramidal cells but enhanced inhibitory synaptic potentials elicited by fast spiking and adapting interneurons at postsynaptic pyramidal cells. Furthermore, CBD restored impaired membrane excitability of PV, CCK and pyramidal cells in a cell type‐specific manner. These neuroprotective effects of CBD were corroborated by immunohistochemistry experiments that revealed a significant reduction in atrophy and death of PV‐ and CCK‐expressing interneurons after CBD treatment.Conclusions and ImplicationsOur data suggest that CBD restores excitability and morphological impairments in epileptic models to pre‐epilepsy control levels through multiple mechanisms to reinstate normal network function.

Section: Methodsmentioning

confidence: 99%

Cannabidiol exerts antiepileptic effects by restoring hippocampal interneuron functions in a temporal lobe epilepsy model

Khan

Shekh‐Ahmad²,

Khalil³

et al. 2018

“…Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Harding et al, 2018), and are permanently archived in the Concise Guide to PHARMACOLOGY 2017/18 (Alexander et al, 2017a,b,c,d). …”

Section: Methodsmentioning

confidence: 99%

Targeting the dopamine D₁ receptor or its downstream signalling by inhibiting phosphodiesterase‐1 improves cognitive performance

Pekcec

Schülert

Stierstorfer

et al. 2018

Background and PurposeInsufficient prefrontal dopamine 1 (D1) receptor signalling has been linked to cognitive dysfunction in several psychiatric conditions. Because the PDE1 isoform B (PDE1B) is postulated to regulate D1 receptor‐dependent signal transduction, in this study we aimed to elucidate the role of PDE1 in cognitive processes reliant on D1 receptor function.Experimental ApproachCognitive performance of the D1 receptor agonist, SKF38393, was studied in the T‐maze continuous alternation task and 5‐choice serial reaction time task. D1 receptor/PDE1B double‐immunohistochemistry was performed using human and rat prefrontal brain sections. The pharmacological activity of the PDE1 inhibitor, ITI‐214, was assessed by measuring the increase in cAMP/cGMP in prefrontal brain tissue and its effect on working memory performance. Mechanistic studies on the modulation of prefrontal neuronal transmission by SKF38393 and ITI‐214 were performed using extracellular recordings in brain slices.Key ResultsSKF38393 improved working memory and attentional performance in rodents. D1 receptor/PDE1B co‐expression was verified in both human and rat prefrontal brain sections. The pharmacological activity of ITI‐214 on its target, PDE1, was demonstrated by its ability to increase prefrontal cAMP/cGMP. In addition, ITI‐214 improved working memory performance. Both SKF38393 and ITI‐214 facilitated neuronal transmission in prefrontal brain slices.Conclusion and ImplicationsWe hypothesize that PDE1 inhibition improves working memory performance by increasing prefrontal synaptic transmission and/or postsynaptic D1 receptor signalling, by modulating prefrontal downstream second messenger levels. These data, therefore, support the use of PDE1 inhibitors as a potential approach for the treatment of cognitive dysfunction.

“…Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Harding et al ., 2018), and are permanently archived in the Concise Guide to PHARMACOLOGY 2017/18 (Alexander et al ., 2017a, 2017b, 2017c). …”

Section: Methodsmentioning

confidence: 99%

Inhibition of protein arginine methyltransferase 3 activity selectively impairs liver X receptor‐driven transcription of hepatic lipogenic genes in vivo

Nahon

Groeneveldt

Geerling

et al. 2018

Background and PurposeAgonists for the liver X receptor (LXR) are considered promising therapeutic moieties in cholesterol‐driven diseases by promoting cellular cholesterol efflux pathways. However, current clinical application of these agents is hampered by concomitant LXR‐induced activation of a lipogenic transcriptional network, leading to hepatic steatosis. Recent studies have suggested that protein arginine methyltransferase 3 (PRMT3) may act as a selective co‐activator of LXR activity. Here, we verified the hypothesis that PRMT3 inhibition selectively disrupts the ability of LXR to stimulate lipogenesis while maintaining its capacity to modulate macrophage cholesterol homeostasis.Experimental ApproachA combination of the LXR agonist T0901317 and palm oil was administered to C57BL/6 mice to maximally stimulate LXR and PRMT3 activity. PRMT3 activity was inhibited using the allosteric inhibitor SGC707.Key ResultsTreatment with SGC707 did not negatively influence the T0901317/palm oil‐induced up‐regulation of the cholesterol efflux ATP‐binding cassette transporter genes, ABCA1 and ABCG1, in peritoneal cells. In contrast, SGC707 treatment was associated with a significant decrease in the hepatic expression of the lipogenic gene fatty acid synthase (−64%). A similar trend was observed for stearoyl‐coenzyme A desaturase and acetyl CoA carboxylase expression (−43%; −56%). This obstruction of lipogenic gene transcription coincided with a significant 2.3‐fold decrease in liver triglyceride content as compared with the T0901317 and palm oil‐treated control group.Conclusion and ImplicationsWe showed that inhibition of PRMT3 activity by SGC707 treatment selectively impairs LXR‐driven transcription of hepatic lipogenic genes, while the positive effect of LXR stimulation on macrophage cholesterol efflux pathways is maintained.