PMID- 31809832 OWN - NLM STAT- MEDLINE DCOM- 20210331 LR - 20210331 IS - 1878-4216 (Electronic) IS - 0278-5846 (Linking) VI - 99 DP - 2020 Apr 20 TI - Activation of 5-HT(1A) postsynaptic receptors by NLX-101 results in functional recovery and an increase in neuroplasticity in mice with brain ischemia. PG - 109832 LID - S0278-5846(19)30687-6 [pii] LID - 10.1016/j.pnpbp.2019.109832 [doi] AB - Pharmacological interventions that selectively activate serotonin 5-hydroxytryptramine-1A (5-HT(1A)) heteroreceptors may prevent or attenuate the consequences of brain ischemic episodes. The present study investigated whether the preferential 5-HT(1A) postsynaptic receptor agonist NLX-101 (a.k.a. F15599) mitigates cognitive and emotional impairments and affects neuroplasticity in mice that are subjected to the bilateral common carotid artery occlusion (BCCAO) model of brain ischemia. The selective serotonin reuptake inhibitor escitalopram (Esc) was used for comparative purposes because it is able to decrease morbidity and improve recovery in stroke patients and ischemic rodents. Sham and BCCAO mice received daily doses of NLX-101 (0.32 mg/kg, i.p) or Esc (20 mg/kg, i.p) for 28 days. During this period, they were evaluated for locomotor activity, anxiety- and despair-related behaviors and hippocampus-dependent cognitive function, using the open field, elevated zero maze, forced swim test and object location test, respectivelly. The mice's brains were processed for biochemical and histological analyses. BCCAO mice exhibited high anxiety and despair-like behaviors and performed worse than controls in the cognitive assessment. BCCAO induced neuronal and dendritic spine loss and decreases in the protein levels of neuronal plasticity markers, including brain-derived neurotrophic factor (BDNF), synaptophysin (SYN), and postsynaptic density protein-95 (PSD-95), in prefrontal cortex (PFC) and hippocampus. NLX-101 and Esc attenuated cognitive impairments and despair-like behaviors in BCCAO mice. Only Esc decreased anxiety-like behaviors due to brain ischemia. Both NLX-101 and Esc blocked the increase in plasma corticosterone levels and, restored BDNF, SYN and PSD-95 protein levels in the hippocampus. Moreover, both compounds impacted positively dentritic remodeling in the hippocampus and PFC of ischemic mice. In the PFC, NLX-101 increased the BDNF protein levels, while Esc in turn, attenuated the decrease in the PSD-95 protein levels induced by BCCAO. The present results suggest that activation of post-synaptic 5-HT(1A) receptors is the molecular mechanism for serotonergic protective effects in BCCAO. Moreover, post-synaptic biased agonists such as NLX-101 might constitute promising therapeutics for treatment of functional and neurodegenerative outcomes of brain ischemia. CI - Copyright (c) 2019 Elsevier Inc. All rights reserved. FAU - Aguiar, Rafael Pazinatto AU - Aguiar RP AD - Department of Pharmacology and Therapeutics, State University of Maringa, Av. Colombo, 5790, CEP 87020-900 Maringa, Parana, Brazil. FAU - Soares, Ligia Mendes AU - Soares LM AD - Department of Pharmacology and Therapeutics, State University of Maringa, Av. Colombo, 5790, CEP 87020-900 Maringa, Parana, Brazil. FAU - Meyer, Erika AU - Meyer E AD - Department of Pharmacology and Therapeutics, State University of Maringa, Av. Colombo, 5790, CEP 87020-900 Maringa, Parana, Brazil. FAU - da Silveira, Fernanda Canova AU - da Silveira FC AD - Department of Pharmacology and Therapeutics, State University of Maringa, Av. Colombo, 5790, CEP 87020-900 Maringa, Parana, Brazil. FAU - Milani, Humberto AU - Milani H AD - Department of Pharmacology and Therapeutics, State University of Maringa, Av. Colombo, 5790, CEP 87020-900 Maringa, Parana, Brazil. FAU - Newman-Tancredi, Adrian AU - Newman-Tancredi A AD - Neurolixis, Inc., Dana Point, CA, USA. FAU - Varney, Mark AU - Varney M AD - Neurolixis, Inc., Dana Point, CA, USA. FAU - Prickaerts, Jos AU - Prickaerts J AD - Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands. FAU - Oliveira, Rubia M Weffort AU - Oliveira RMW AD - Department of Pharmacology and Therapeutics, State University of Maringa, Av. Colombo, 5790, CEP 87020-900 Maringa, Parana, Brazil. Electronic address: rmmwoliveira@uem.br. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20191203 PL - England TA - Prog Neuropsychopharmacol Biol Psychiatry JT - Progress in neuro-psychopharmacology & biological psychiatry JID - 8211617 RN - 0 (3-chloro-4-fluorophenyl-(4-fluoro-4-(((5-methylpyrimidin-2-ylmethyl)amino)methyl)piperidin-1-yl)methanone) RN - 0 (Htr1a protein, mouse) RN - 0 (Piperidines) RN - 0 (Pyrimidines) RN - 0 (Serotonin 5-HT1 Receptor Agonists) RN - 112692-38-3 (Receptor, Serotonin, 5-HT1A) SB - IM MH - Animals MH - Brain Ischemia/drug therapy/*metabolism MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Neuronal Plasticity/*drug effects/physiology MH - Piperidines/pharmacology/*therapeutic use MH - Pyrimidines/pharmacology/*therapeutic use MH - Receptor, Serotonin, 5-HT1A/*metabolism MH - Recovery of Function/*drug effects/physiology MH - Serotonin 5-HT1 Receptor Agonists/pharmacology/*therapeutic use OTO - NOTNLM OT - 5-HT(1A) receptor OT - Brain ischemia OT - NLX-101 OT - Neuroprotection COIS- Declaration of Competing Interest Adrian Newman-Tancredi and Mark Varney are employees and stockholders of Neurolixis. EDAT- 2019/12/07 06:00 MHDA- 2021/04/01 06:00 CRDT- 2019/12/07 06:00 PHST- 2019/08/14 00:00 [received] PHST- 2019/11/18 00:00 [revised] PHST- 2019/12/01 00:00 [accepted] PHST- 2019/12/07 06:00 [pubmed] PHST- 2021/04/01 06:00 [medline] PHST- 2019/12/07 06:00 [entrez] AID - S0278-5846(19)30687-6 [pii] AID - 10.1016/j.pnpbp.2019.109832 [doi] PST - ppublish SO - Prog Neuropsychopharmacol Biol Psychiatry. 2020 Apr 20;99:109832. doi: 10.1016/j.pnpbp.2019.109832. Epub 2019 Dec 3.