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Potential anti-arthritic and analgesic properties of essential oil and viridiflorol obtained from Allophylus edulis leaves in mice

de Matos Balsalobre, Natália; Dos Santos, Elisangela; Mariano Dos Santos, Sidney; Arena, Arielle Cristina; Konkiewitz, Elisabete Castelon; Ziff, Edward Benjamin; Nazari Formagio, Anelise Samara; Leite Kassuya, Candida Aparecida
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 ( 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, 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.
PMID: 36223847
ISSN: 1872-7573
CID: 5352082

Natural Products as Sources of New Analgesic Drugs [Editorial]

Arena, Arielle Cristina; Leite Kassuya, Candida Aparecida; Konkiewitz, Elisabete Castelon; Ziff, Edward Benjamin
PMID: 35154353
ISSN: 1741-427x
CID: 5175552

Phosphorylation of the AMPA receptor subunit GluA1 regulates clathrin-mediated receptor internalization

Sathler, Matheus F; Khatri, Latika; Roberts, Jessica P; Schmidt, Isabella G; Zaytseva, Anastasiya; Kubrusly, Regina C C; Ziff, Edward B; Kim, Seonil
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.
PMID: 34369573
ISSN: 1477-9137
CID: 5039312

Contribution of spathulenol to the anti-nociceptive effects of Psidium guineense

Dos Santos, Elisangela; Radai, Joyce Alencar Santos; do Nascimento, Kamilla Felipe; Formagio, Anelise Samara Nazari; de Matos Balsalobre, Natália; Ziff, Edward Benjamin; Castelon Konkiewitz, Elisabete; Kassuya, Candida Aparecida Leite
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.
PMID: 32912110
ISSN: 1476-8305
CID: 4589502

Protein synthesis inhibition promotes nitric oxide generation and activation of CGKII-dependent downstream signaling pathways in the retina

Cossenza, Marcelo; Socodato, Renato; Mejía-García, Telmo A; Domith, Ivan; Portugal, Camila C; Gladulich, Luis F H; Duarte-Silva, Aline T; Khatri, Latika; Antoine, Shannon; Hofmann, Franz; Ziff, Edward B; Paes-de-Carvalho, Roberto
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.
PMID: 32360667
ISSN: 1879-2596
CID: 4439072

Regulation of AMPA receptor trafficking and exit from the endoplasmic reticulum

Pick, Joseph E; Ziff, Edward B
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.
PMID: 29545119
ISSN: 1095-9327
CID: 2994302

Sucrose withdrawal induces depression and anxiety-like behavior by Kir2.1 upregulation in the nucleus accumbens

Kim, Seonil; Shou, Jiayi; Abera, Sinedu; Ziff, Edward B
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.
PMID: 29191750
ISSN: 1873-7064
CID: 3015052

Dissociation, Delusion and the Splitting of the Self in The Trial by Franz Kafka: Phenomenology and Neurobiology of Schizophrenia

Castelon Konkiewitz, Elisabete; Ziff, Edward Benjamin
In this essay, we propose an association between Franz Kafka's novel, The Trial, and phenomenological and neurobiological processes in schizophrenia. We begin by presenting a summary of the plot, pointing to some of its remarkable literary aspects. We next compare the mental processes of dissociation, disorientation and delusion as represented in the novel with phenomenological processes that take place in the prodromal states of schizophrenia. We discuss how such disorders of the self and disorders of thought, both crucial aspects of the schizophrenic experience, appear in The Trial and in other literary and private writings by Franz Kafka. We relate how these disorders may arise from the false attribution of salience and false associative learning caused by hyperactivity of dopaminergic function associated with chaotic firing of dopaminergic neurons. Finally, we show how Kafka leads not just the protagonist of The Trial, but even more the reader to experience a quasi-delusional state. We discuss the relationship between the perturbation of thought and disorientation of mind evoked by the novel in the reader and the need of our brains for empathy and predictability.
PMID: 30336466
ISSN: 1662-2804
CID: 3368732

Letter to His Father by Franz Kafka: Literary Reconstruction of a Traumatic Childhood?

Castelon Konkiewitz, Elisabete; Ziff, Edward B
Franz Kafka's Letter to His Father is one of the greatest examples in world literature of memory of a traumatic childhood. In it, the author takes a retrospective journey through his life, recollecting and analyzing the reasons for the estrangement and hostility between a father and a son. This essay considers Letter to His Father in the light of current knowledge about autobiographical memory. The essay first sets forth basic aspects of Kafka's life in order to place Letter to His Father in the context of Kafka's biography, and then presents Kafka's relevance to the literature and thought of the twentieth and twenty-first centuries. The essay then considers the different forms of childhood abuse and their consequences in light of evidence from neurodevelopmental psychology. We present evidence about the relationship between trauma and the construction of self-image. Furthermore, we discuss the subjectivity of Kafka's recollections from the perspective of recent advances in neurobiology. Memory is shown to be dynamic, selective, inherently malleable and dependent on perception, which is a subjective construction, in which the brain interprets and gives coherence to experienced stimuli. We consider the inaccuracy of memory, which is related to neuroplastic changes in the brain that take place over time: consolidation, reconsolidation and transformation. Finally, the relationship between literature and autobiography in the Kafkaesque universe is considered.
PMID: 30419567
ISSN: 1662-2804
CID: 3429292

Limonene reduces hyperalgesia induced by gp120 and cytokines by modulation of IL-1 beta and protein expression in spinal cord of mice

Piccinelli, Ana Claudia; Morato, Priscila Neder; Dos Santos Barbosa, Marcelo; Croda, Julio; Sampson, Jared; Kong, Xiangpeng; Konkiewitza, Elisabete Castelon; Ziff, Edward B; Amaya-Farfan, Jaime; Kassuya, Candida Aparecida Leite
AIMS: We have investigated the antihyperalgesic effects of limonene in mice that received intrathecal injection of gp120. MAIN METHODS: Male Swiss mice received gp120, IL-1beta or TNF-alpha intrathecally or sterile saline as a control. A mechanicalsensitivity test was performed at 2 and 3h after the injection. Spinal cord and blood samples were isolated for protein quantification. KEY FINDINGS: Intrathecal administration of gp120 increased mechanical sensitivity measured with an electronic Von Frey apparatus, at 2 and 3h after the injections. Limonene administered orally prior to gp120 administration significantly decreased this mechanical sensitivity at 3h after the gp120 injection. In addition, intrathecal injection of gp120 increased IL-1beta and IL-10 in serum, and limonene prevented the ability of gp120 to increase these cytokines. Limonene also inhibited TNF-alpha and IL-1beta-induced mechanical hyperalgesia. Western blot assay demonstrated limonene was capable of increasing SOD expression in the cytoplasm of cells from spinal cord at 4h after intrathecal IL-1beta injection. SIGNIFICANCE: These results demonstrate that gp120 causes mechanical hyperalgesia and a peripheral increase in IL-1beta and IL-10, and that prior administration of limonene inhibits these changes. Also limonene modulates the activation of SOD expression in the spinal cord after spinal IL-1beta application. The ability of limonene to inhibit the mechanical hyperalgesia induced by gp120, TNF-alpha and IL-1beta emphasizes the anti-inflammatory action of limonene, specifically its ability to inhibit cytokine production and its consequences.
PMID: 27888114
ISSN: 1879-0631
CID: 2314612