Faculty Bibliography

BACKGROUND:Guettarda viburnoides Cham. & Schltdl., "veludinho do campo", is used in the Brazilian Amazon for its effects on the central nervous system (CNS) as a "brain tonic"; however, scientific evidence is needed to elucidate its ethnobotanical uses. OBJECTIVE:This study evaluated the neurobehavioural effects of an ethanolic extract of G. viburnoides (EEGV). Molecular docking, microchemical and morphoanatomical features of the species were investigated. METHODS:EEGV was investigated by UHPLC‒MS/MS and dereplication and molecular network were investigated using platforms available for natural product chemistry. For the in vivo assay, EEGV was administered to mice orally (3, 30 or 100 mg/kg). The effect of EEGV on spatial memory was measured using the Morris water maze test in mice with scopolamine-induced amnesia. The depression- and anxiety-like effects were assessed by forced swimming, tail suspension, marble burying and elevated plus maze tests. The AChE inhibition was evaluated in the brains of treated mice and molecular docking simulations were carried out with the main constituents. The leaves and stems of G. viburnoides were analysed via optical microscopy, scanning electron microscopy and energy dispersive X-ray spectroscopy. RESULTS:Secoxyloganin, grandifloroside, hyperin/or isoquercitrin, uncaric acid and ursolic acid were identified by UHPLC‒MS/MS. Molecular networking by three flavonoids, three triterpenes, two coumarins, two iridoids, and one phenolic acid. EEGV reversed these scopolamineinduced effects. In the forced swim and tail suspension test, EEGV (30 and 100 mg/kg) significantly reduced the immobility time. EEGV significantly reduced the number of buried marbles, while in the elevated plus maze test, no changes were observed compared to the Sco group. AChE activity was altered in the hippocampus. Studies of the molecular coupling of iridoid glycosides (grandifloroside and secoxyloganin) and flavonoid hyperin with AChE revealed significant interactions, corroborating the activity indicated by the inhibition assay. CONCLUSIONS:These results might be in accordance with medicinal use for neuroprotetor effects and important microchemical and micromorphological data that support the identification and quality control of G. viburnoides.

Species of the genus Psychotria are used in popular medicine for pain, inflammatory symptoms, and mental disorders. Psychotria capillacea (Müll. Arg.) Standl. (Rubiaceae) is commonly known as coffee and some scientific studies have demonstrated its therapeutic potential. The goal of this study was to investigate the anti-inflammatory and neuroprotective effects, and acetylcholinesterase (AChE) inhibitory activity of a methanolic extract obtained from leaves of P. capillacea (MEPC), as well as the micromorphology and histochemistry of the leaves and stems of this plant. In addition, the MEPC was analyzed by UHPLC-MS/MS and the alkaloidal fraction (AF) obtained from the MEPC was tested in a mouse model of inflammation. MEPC contained three indole alkaloids, one sesquiterpene (megastigmane-type) and two terpene lactones. MEPC (3, 30 and 100 mg/kg) and AF (3 and 30 mg/kg) were evaluated in inflammation models and significantly inhibited edema at 2 h and 4 h, mechanical hyperalgesia after 4 h and the response to cold 3 h and 4 h after carrageenan injection. Scopolamine significantly increased the escape latency, and reduced the swimming time and number of crossings in the target quadrant and distance, while MEPC (3, 30 and 100 mg/kg), due to its neuroprotective actions, reversed these effects. AChE activity was significantly decreased in the cerebral cortex (52 ± 3%) and hippocampus (60 ± 3%), after MEPC administration. Moreover, micromorphological and histochemical information was presented, to aid in species identification and quality control of P. capillacea. The results of this study demonstrated that P. capillacea is an anti-inflammatory and antihyperalgesic agent that can treat acute disease and enhance memory functions in mouse models.

BACKGROUND:In this paper, we argue that recent unprecedented social changes arising from social media and the internet represent powerful behavioral and environmental forces that are driving human evolutionary adaptive responses in a way that might reshape our brain and the way it perceives reality and interacts with it. These forces include decreases in physical activity, decreases in exposure to light, and face-to-face social interactions, as well as diminished predictability in biological rhythms (i.e., the sleep cycle is no longer dictated by natural light exposure and season). SUMMARY/CONCLUSIONS:We discuss the roles of stress and of creativity and adaptability in Homo sapiens evolution and propose mechanisms for human adaptation to the new forces including epigenetic mechanisms, gene-culture coevolution, and novel mechanisms of evolution of the nervous system. KEY MESSAGES/CONCLUSIONS:We present the provocative idea that evolution under the strong selective pressures of today's society could ultimately enable H. sapiens to thrive despite social, physical, circadian, and cultural deprivation and possible neurological disease, and thus withstand the loss of factors that contribute to H. sapiens survival of today. The new H. sapiens would flourish under a lifestyle in which the current form would feel undervalued and replaceable.

ETHNOPHARMACOLOGICAL RELEVANCE/BACKGROUND:Viridiflorol was identified and isolated from the essential oil of Allophylus edulis leaves (EOAE). A. edulis was used as "tereré", which is a drink made by the infusion of herbs in cold water, to treat pain (toothache and headache). All anti-nociceptive (analgesic) and anti-arthritic properties of EOAE and viridiflorol have not been completely scientifically clarified. AIM OF THE STUDY/OBJECTIVE:The aim of the present study was to investigate the analgesic (anti-hyperalgesic and anti-nociceptive) and anti-arthritic properties of EOAE and viridiflorol using in vivo models. MATERIALS AND METHODS/METHODS:The oral administration (p.o.) of EOAE (30, 100 and 300 mg/kg), viridiflorol (30, 100 and 200 mg/kg), morphine (1 mg/kg, subcutaneous route (s.c.)) and the intraplantar (local) administration (i.pl.) of viridiflorol (100 μg/paw) were tested using formalin model in Swiss mice. EOAE (100 mg/kg, p.o.), viridiflorol (200 mg/kg, p.o.), and dexamethasone (1 mg/kg, s.c.) were tested by zymosan-articular inflammation and in open-field models. Viridiflorol (0.3, 20 and 200 μg/paw) was also tested in carrageenan model, and viridiflorol (200 μg/paw) was also tested in tumor necrosis factor-α (TNF-α), and dopamine (DOPA) models. RESULTS:The oral administration of EOAE (100 and 300 mg/kg, p.o.), viridiflorol (200 mg/kg, p.o.), morphine (1 mg/kg, s.c.) (MOR) and local administration of viridiflorol (100 μg/paw) significantly inhibited edema and nociception in formalin model. Oral treatments with EOAE and viridiflorol (200 mg/kg) did not cause motor impairment in the open field test since they did not reduce locomotor activity. EOAE, viridiflorol and dexamethasone significantly reduced mechanical hyperalgesia, edema, total leukocytes, polymorphonuclear cells, nitric oxide and protein exudation in the zymosan-induced articular inflammation model. The local administration of viridiflorol (200 μg/paw, i.pl.) significantly inhibited mechanical hyperalgesia and edema induced by carrageenan, TNF-α and DOPA. CONCLUSIONS:This study confirms the potential anti-arthritic, anti-nocicepttive and anti-hyperalgesic properties of EOAE and viridiflorol. These properties could explain, at least in part, the folk use of A. edulis against including pain (toothache and headache). Viridiflorol could be partially responsible for the EOAE anti-hyperalgesic, anti-nociceptive and anti-arthritic properties and its mechanism of action could involve the inhibition of TNF-α and DOPA pathways.

Synaptic strength is altered during synaptic plasticity by controlling the number of AMPA receptors (AMPARs) at excitatory synapses. During long-term potentiation and synaptic upscaling, AMPARs are accumulated at synapses to increase synaptic strength. Neuronal activity leads to phosphorylation of AMPAR subunit GluA1 (also known as GRIA1) and subsequent elevation of GluA1 surface expression, either by an increase in receptor forward trafficking to the synaptic membrane or a decrease in receptor internalization. However, the molecular pathways underlying GluA1 phosphorylation-induced elevation of surface AMPAR expression are not completely understood. Here, we employ fluorescence recovery after photobleaching (FRAP) to reveal that phosphorylation of GluA1 serine 845 (S845) predominantly plays a role in receptor internalization, rather than forward trafficking, during synaptic plasticity. Notably, internalization of AMPARs depends upon the clathrin adaptor AP2, which recruits cargo proteins into endocytic clathrin-coated pits. In fact, we further reveal that an increase in GluA1 S845 phosphorylation upon two distinct forms of synaptic plasticity diminishes the binding of the AP2 adaptor, reducing internalization and resulting in elevation of GluA1 surface expression. We thus demonstrate a mechanism of GluA1 phosphorylation-regulated clathrin-mediated internalization of AMPARs.

Objectives: Araçá-verdadeiro is the popular name of Psidium guineense (Myrtaceae), whose fruits and leaves are used in Brazilian folk medicine for treatment of inflammation and pain. The focus of the present research was an investigation of the anti-nociceptive, and anti-inflammatory effects of the essential oil from P. guineense (EOPG) leaves, and of spathulenol. The anxiolytic and antidepressive effects associated with chronic pain were also investigated in models of acute or persistent nociception or/and inflammatory pain. Methods and Results: Oral treatment with EOPG (10-100 mg/kg) or spathulenol (10 mg/kg) significantly inhibited formalin-induced nociceptive responses, both sensitivity to cold and edema. Oral treatment with EOPG (10 mg/kg) and spathulenol (10 mg/kg) did not reduce locomotor activity (open field test). Local administration of spathulenol (1000 µg/paw) significantly prevented formalin-induced nociceptive sensitivity to cold and paw edema, and carrageenan-induced mechanical hyperalgesia, paw edema and sensitivity to cold. In the Freund's complete adjuvant (CFA) model, oral treatment with EOPG (10 mg/kg) or spathulenol (10 mg/kg) for 21 days significantly inhibited all analyzed parameters. The percentage maximal inhibition by spathulenol was 76.00% (mechanical hyperalgesia), 71.90% (cold response), 85.00% (edema), 77.16% (myeloperoxidase activity), 97.72% (time in the closed arms in the elevated plus maze), and 49.00% (immobility time in the tail suspension test), in the CFA model. Models employed male Swiss mice, except for the CFA test, which employed C57bL6 male mice (n=6 /group). Conclusion: This study demonstrates that EOPG is an anti-nociceptive and anti-hyperalgesic agent, in acute and continuous treatment, and an anxiolytic and antidepressive agent when tested with the chronic pain experimental state.

Nitric oxide is an important neuromodulator in the CNS, and its production within neurons is modulated by NMDA receptors and requires a fine-tuned availability of L-arginine. We have previously shown that globally inhibiting protein synthesis mobilizes intracellular L-arginine "pools" in retinal neurons, which concomitantly enhances neuronal nitric oxide synthase-mediated nitric oxide production. Activation of NMDA receptors also induces local inhibition of protein synthesis and L-arginine intracellular accumulation through calcium influx and stimulation of eucariotic elongation factor type 2 kinase. We hypothesized that protein synthesis inhibition might also increase intracellular L-arginine availability to induce nitric oxide-dependent activation of downstream signaling pathways. Here we show that nitric oxide produced by inhibiting protein synthesis (using cycloheximide or anisomycin) is readily coupled to AKT activation in a soluble guanylyl cyclase and cGKII-dependent manner. Knockdown of cGKII prevents cycloheximide or anisomycin-induced AKT activation and its nuclear accumulation. Moreover, in retinas from cGKII knockout mice, cycloheximide was unable to enhance AKT phosphorylation. Indeed, cycloheximide also produces an increase of ERK phosphorylation which is abrogated by a nitric oxide synthase inhibitor. In summary, we show that inhibition of protein synthesis is a previously unanticipated driving force for nitric oxide generation and activation of downstream signaling pathways including AKT and ERK in cultured retinal cells. These results may be important for the regulation of synaptic signaling and neuronal development by NMDA receptors as well as for solving conflicting data observed when using protein synthesis inhibitors for studying neuronal survival during development as well in behavior and memory studies.

A fundamental property of the brain is its ability to modify its function in response to its own activity. This ability for self-modification depends to a large extent on synaptic plasticity. It is now appreciated that for excitatory synapses, a significant part of synaptic plasticity depends upon changes in the post synaptic response to glutamate released from nerve terminals. Modification of the post synaptic response depends, in turn, on changes in the abundances of AMPA receptors in the post synaptic membrane. In this review, we consider mechanisms of trafficking of AMPA receptors to and from synapses that take place in the early trafficking stages, starting in the endoplasmic reticulum (ER) and continuing into the secretory pathway. We consider mechanisms of AMPA receptor assembly in the ER, highlighting the role of protein synthesis and the selective properties of specific AMPA receptor subunits, as well as regulation of ER exit, including the roles of chaperones and accessory proteins and the incorporation of AMPA receptors into COPII vesicles. We consider these processes in the context of the mechanism of mGluR LTD and discuss a compelling role for the dendritic ER membrane that is found proximal to synapses. The review illustrates the important, yet little studied, contribution of the early stages of AMPA receptor trafficking to synaptic plasticity.

Dieting induces depression and anxiety among other emotional symptoms. Animal models indicate that repeated access to palatable foods such as sugar induces depression and anxiety-like behavior when the food is no longer available. However, the neurobiological mechanisms of how dietary restriction influences mood have not been fully understood. We used the two-bottle sucrose choice paradigm as an overeating and withdrawal model. Withdrawal after lengthy sucrose overeating elicited depression and anxiety-like behavior, which was reversed by sucrose reinstatement. In the nucleus accumbens (NAc) of sucrose withdrawal animals, dopamine levels and cAMP response element binding protein (CREB) activity were significantly reduced, while the inwardly rectifying K⁺channel, Kir2.1, was significantly elevated. In addition, overexpression of Kir2.1 selectively in neurons expressing dopamine D1 receptors was sufficient to induce negative mood-linked behavior in the absence of sucrose overeating experience. As elevated K⁺channels reduce neuronal excitability, a sucrose withdrawal-induced increase in Kir2.1 expression is able to decrease NAc activity, which provides a cellular basis for depression and anxiety-like behavior in animals.