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5-HT1A serotonin receptors may play a role in cognitive function changes related to advanced age. Here, we investigated the effects of acute and repeated treatment with NLX-101 (F15599), a postsynaptic 5-HT1A receptor-biased agonist, and F13714, a presynaptic 5-HT1A receptor-biased agonist on spatial object pattern separation (OPS) in aged (22-24 months) rats. Neuroplasticity markers including brain-derived neurotrophic factor, PSD95, synaptophysin, and doublecortin were evaluated in the hippocampus. Unlike younger rats, aged rats were incapable of discriminating any new position of the objects in the arena, reflecting the detrimental effect of aging on pattern separation. However, aged animals treated with NLX-101 showed a significant cognitive improvement in the OPS test, accompanied by increases in hippocampal brain-derived neurotrophic factor and PSD95 protein levels. In contrast, no improvement in OPS performance was observed when aged rats received F13714. Both F13714 and NLX-101 increased the number of newborn neurons in the hippocampi of aged rats. These findings provide a rationale for targeting post-synaptic 5-HT1A as a treatment for cognitive deficits related to aging.

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Cerebral ischemia due to stroke or cardiac arrest greatly affects daily functioning and the quality of life of patients and has a high socioeconomic impact due to the surge in their prevalence. Advances in the identification of an effective pharmacotherapy to promote neuroprotection and recovery after a cerebral ischemic insult are, however, limited. The serotonin 1A (5-HT1A) receptor has been implicated in the regulation of several brain functions, including mood, emotions, memory, and neuroplasticity, all of which are deleteriously affected by cerebral ischemia. This review focuses on the specific roles and mechanisms of 5-HT1A receptors in neuroprotection in experimental models of cerebral ischemia. We present experimental evidence that 5-HT1A receptor agonists can prevent neuronal damage and promote functional recovery induced by focal and transient global ischemia in rodents. However, indiscriminate activation of pre-and postsynaptic by non-biased 5-HT1A receptor agonists may be a limiting factor in the anti-ischemic clinical efficacy of these compounds since 5-HT1A receptors in different brain regions can mediate diverging or even contradictory responses. Current insights are presented into the 'biased' 5-HT1A post-synaptic heteroreceptor agonist NLX-101 (also known as F15599), a compound that preferentially and potently stimulates postsynaptic cortical pyramidal neurons without inhibiting firing of serotoninergic neurons, as a potential strategy providing neuroprotection in cerebral ischemic conditions.

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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.

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To investigate the hepatoprotective effect of Cymbopogon citratus or lemongrass essential oil (LGO), it was used in an animal model of acute liver injury induced by acetaminophen (APAP). Swiss mice were pretreated with LGO (125, 250 and 500[Formula: see text]mg/kg) and SLM (standard drug, 200[Formula: see text]mg/kg) for a duration of seven days, followed by the induction of hepatotoxicity of APAP (single dose, 250[Formula: see text]mg/kg). The liver function markers alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and gamma-glutamyl transferase were determined to evaluate the hepatoprotective effects of the LGO. The livers were used to determine myeloperoxidase (MPO) activity, nitric oxide (NO) production and histological analysis. The effect of LGO on leukocyte migration was evaluated in vitro. Anti-oxidant activity was performed by assessing the free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH) in vitro. LGO pretreatment decreased significantly the levels of ALT, AST and ALP compared with APAP group. MPO activity and NO production were decreased. The histopathological analysis showed an improved of hepatic lesions in mice after LGO pretreatment. LGO inhibited neutrophil migration and exhibited anti-oxidant activity. Our results suggest that LGO has protective activity against liver toxicity induced by paracetamol.

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Genome-wide gene expression profiling of cancers has consistently identified the FOXM1 as one of the most commonly upregulated genes in cancer cells that plays an essential role in the regulation of a wide spectrum of biological processes, including inhibition of apoptosis. Since the anticancer activity of EUG reported in the literature is related to induction of apoptosis in cancer cells, we hypothesized that there is a correlation between the EUG-induced apoptosis effect and downregulation of FOXM1. A series of experiments were conducted to evaluate the effect of EUG on cellular viability of cancer cells (MTT) and its potential regulatory effect on FOXM1 protein levels (western blots). Our findings confirm the anticancer effect of EUG on different human cancer cell lines as previously reported in the literature (SKBR3 LC50: 318.6; HT29 LC50: 525.5; and HepG2 LC50: 2090.0 µM). However, we demonstrated that EUG does not regulate the FOXM1. The results evidenced the anticancer effect of EUG on three cancer cell lines and showed that the EUG- apoptosis induced effect is not related to regulation of FOXM1 at the protein level. Further studies must be done to provide information on the mechanism of action of this agent.

Estudos do genoma de células tumorais identificaram o FOXM1 como o fator de transcrição mais expresso, desempenhando papel essencial em uma gama de processos biológicos, incluindo a inibição da apoptose celular. A atividade anticarcinogênica do EUG, relatada na literatura, está relacionada à indução de apoptose em células cancerosas, por isso geramos a hipótese de que pode existir correlação entre este efeito indutor de apoptose e a supressão do FOXM1. Um conjunto de experimentos foi realizado com o objetivo de avaliar o efeito do EUG na viabilidade celular (MTT) e o potencial regulatório sobre o nível de proteínas do FOXM1, em células cancerosas (western blots). Nossos resultados corroboram o efeito anticancerígeno do EUG relatado na literatura em diferentes linhagens celulares (SKBR3 LC50: 318.6; HT29 LC50: 525.5; e HepG2 LC50: 2090.0 µM). Entretanto ficou demonstrado que o EUG não interfere no nível proteico do FOXM1. Em nosso estudo demonstramos o efeito citotóxico do EUG em três linhagens celulares de câncer, sendo evidenciado que o efeito indutor de apoptose promovido pelo mesmo não é dependente da regulação do fator de transcrição FOXM1. Estudos mais detalhados serão conduzidos no intuito de esclarecer os mecanismos de ação desde agente anticarcinogênico.

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Acute liver damage caused by acetaminophen overdose is a significant clinical problem and could benefit from new therapeutic strategies. Objective. This study investigated the hepatoprotective effect of Thymus vulgaris essential oil (TEO), which is used popularly for various beneficial effects, such as its antiseptic, carminative, and antimicrobial effects. The hepatoprotective activity of TEO was determined by assessing serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) in mice. Their livers were then used to determine myeloperoxidase (MPO) enzyme activity and subjected to histological analysis. In vitro antioxidant activity was evaluated by assessing the free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH•)-scavenging effects of TEO and TEO-induced lipid peroxidation. TEO reduced the levels of the serum marker enzymes AST, ALT, and ALP and MPO activity. The histopathological analysis indicated that TEO prevented acetaminophen-induced necrosis. The essential oil also exhibited antioxidant activity, reflected by its DPPH radical-scavenging effects and in the lipid peroxidation assay. These results suggest that TEO has hepatoprotective effects on acetaminophen-induced hepatic damage in mice.