TY - JOUR
T1 - Activation of 5-HT1A postsynaptic receptors by NLX-101 results in functional recovery and an increase in neuroplasticity in mice with brain ischemia
AU - Aguiar, Rafael Pazinatto
AU - Soares, Ligia Mendes
AU - Meyer, Erika
AU - da Silveira, Fernanda Canova
AU - Milani, Humberto
AU - Newman-Tancredi, Adrian
AU - Varney, Mark
AU - Prickaerts, Jos
AU - Weffort Oliveira, Rubia M.
PY - 2020/4/20
Y1 - 2020/4/20
N2 - Pharmacological interventions that selectively activate serotonin 5-hydroxytryptramine-1A (5-HT1A) heteroreceptors may prevent or attenuate the consequences of brain ischemic episodes. The present study investigated whether the preferential 5-HT1A 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-HT1A 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.
AB - Pharmacological interventions that selectively activate serotonin 5-hydroxytryptramine-1A (5-HT1A) heteroreceptors may prevent or attenuate the consequences of brain ischemic episodes. The present study investigated whether the preferential 5-HT1A 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-HT1A 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.
KW - NLX-101
KW - 5-HT1A receptor
KW - Brain ischemia
KW - Neuroprotection
KW - GLOBAL CEREBRAL-ISCHEMIA
KW - TRANSIENT FOREBRAIN ISCHEMIA
KW - NEUROPROTECTIVE MELATONIN TREATMENT
KW - CHRONICALLY STRESSED MICE
KW - HIPPOCAMPAL CA1 REGION
KW - LONG-TERM
KW - PYRAMIDAL NEURONS
KW - SPINE DENSITY
KW - RAT-BRAIN
KW - SYNAPTOPHYSIN EXPRESSION
U2 - 10.1016/j.pnpbp.2019.109832
DO - 10.1016/j.pnpbp.2019.109832
M3 - Article
C2 - 31809832
SN - 0278-5846
VL - 99
JO - Progress in Neuro-Psychopharmacology & Biological Psychiatry
JF - Progress in Neuro-Psychopharmacology & Biological Psychiatry
M1 - 109832
ER -