Orientador: Eliana Marisa ganem / Resumo: A espasticidade leva a perda na qualidade de vida, capacidade funcional do indivíduo e a alterações psicossociais. O baclofeno é fármaco relaxante muscular de ação central, utilizado no tratamento da espasticidade e é substância análoga ao ácido gama amino-butírico (GABA). Sua administração por via subaracnoidea permite que doses pequenas sejam utilizadas, minimizando efeitos adversos. A pesquisa consistiu em determinar os efeitos da administração de baclofeno em dose única, no espaço subaracnoideo de coelhos, sobre a medula espinal e as meninges. Foram utilizados coelhos, divididos em três grupos: G1, G2 e G3, com injeção no espaço subaracnoideo de soro fisiológico, baclofeno 100 μg e 200 μg respectivamente. Posteriormente foram realizadas as análises histológicas das meninges e medula dos coelhos. Os resultados da presente pesquisa mostram que o baclofeno, independe da dose administrada, causou lesão de tecido nervoso e de meninges em 20% (n=8) dos coelhos estudados. As alterações histológicas foram predominantemente observadas na região posterior das meninges. Podemos concluir que neste modelo experimental em coelhos o baclofeno desencadeou reação inflamatória no tecido nervoso e nas meninges. / Abstract: Spasticity leads to a reduced quality of life, functional capacity limitations, and changes in the psychosocial well-being of an individual. Baclofen is a centrally acting muscle relaxant that is used in the treatment of spasticity and is an analog of gammaamino-butyric acid. Its administration via the subarachnoid route allows the use of small doses, thus minimizing adverse effects. The aim of the study was to determine the effects of administration of a single dose of baclofen into the subarachnoid space of rabbits, on the spinal cord and meninges. Methods: The rabbits were divided into three groups. The first group (G1) was injected with saline solution. The second and third groups (G2 and G3) received 100 and 200 μg of baclofen in the subarachnoid space, respectively. Histological analysis of the meninges and spinal cord in rabbits was subsequently performed. The present findings showed that baclofen, regardless of the administered dose, caused damage to the nerve tissue and meninges in 20% (n = 8) of the tested rabbits. The histological changes were predominantly observed in the posterior portion of the meninges. We conclude that, in this rabbit experimental model, baclofen caused an inflammatory reaction in the nervous tissue and meninges. / Doutor

Made available in DSpace on 2014-06-11T19:35:05Z (GMT). No. of bitstreams: 0 Previous issue date: 2008-10-21Bitstream added on 2014-06-13T19:44:54Z : No. of bitstreams: 1 fukushima_fb_dr_botfm.pdf: 568146 bytes, checksum: 4ddf6ccf6598e54e706aa67da8b77e4d (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Universidade Estadual Paulista (UNESP) / A amitriptilina é o protótipo dos antidepressivos tricíclicos, classe de fármaco muito utilizada no tratamento da dor neuropática. Tem por propriedade principal a inibição da recaptação de serotonina e noradrenalina, além de interagir com diversos outros receptores. Estudos recentes demonstraram que os antidepressivos tricíclicos são potentes bloqueadores dos canais de sódio, potássio e cálcio, apresentando propriedades semelhantes aos anestésicos locais. Assim existe potencial para que esta classe farmacológica possa ser utilizada no neuroeixo como adjuvante anestésico local ou no tratamento de síndromes dolorosas neuropáticas refratárias. Entretanto, até o presente momento, não há consenso quanto a neurotoxicidade desta classe farmacológica sobre a medula e as meninges. O objetivo desta pesquisa foi avaliar a toxicidade da amitriptilina sobre a medula e as meninges quando administrada pela via subaracnóidea em cães. Método: Vinte e um animais foram randomizados em três grupos que receberam pela via subaracnóidea: Grupo 1 - Solução fisiológica 0,9%; Grupo 2 - solução de amitriptilina 5 mmol.ml-1; Grupo 3- solução de amitriptilina 10 mmol.ml-1. A punção subaracnóidea foi realizada no espaço intervertebral L6-L7. O volume da solução injetada foi de 1 ml. Os animais foram avaliados após uma hora da administração do fármaco e durante os 21 dias que permaneceram em cativeiro quanto ao tônus do esfíncter anal, bloqueio motor e sensibilidade dolorosa. Os animais foram sacrificados por eletrocussão sob anestesia. A medula e as meninges fixadas com solução de formalina 10%, coradas pelos métodos hematoxilina-eosina e tricrômico de Masson, para posterior analise histológica. O estudo foi duplamente encoberto. Para avaliação estatística foi utilizada a análise de variância. Resultados: Durante o período de observação de 21 dias os animais... / Amitriptyline is the prototype drug of the tricyclic antidepressants, which are commonly used as adjuvant medications in the treatment of neuropathic pain syndromes. It is an inhibitor of the reuptake of serotonin and norepinephrine, as well as a blocking agent for great number of receptors. Recent reports have demonstrated tricyclic antidepressants as potent blocking agents for voltage-dependent ionic Na+, K+ and Ca++ channels. Presenting a local anesthetic property. Hence there is a potential role for the intra-spinal use of amitriptyline as an adjuvant in neuroaxial anesthesia and in the treatment of refractory neuropathic pain. Nevertheless, to our knowledge there is no known information regarding the possible neural and meningeal effects of neuraxial amitriptyline administration. Therefore, we conducted a study to evaluate the neural and meningeal toxicities profiles of the intraspinal administration of amitriptyline to dogs. Methods: 21 Dogs were randomly selected for one of three groups: Group 1- 0,9% saline; Group 2- amitriptyline 5 mmol.ml-1 solution; Group 3- amitriptyline 10 mmol.ml-1 solution. In each of the groups one milliliter of the randomized solution was intraspinally administered by an investigator blinded for the intervention group. The dogs were evaluated one hour after awaking from the anesthesia and the following 21 days in the three following domains: anal sphincter tone, motor blockage and pain. The dogs were sacrificed by electrocution under anesthesia, the spinal cords were removed, fixed in 10% Formalin solution, stained by hematoxylin and eosin and Masson's trichrome technique for posterior histological analysis. We used analysis of variance to assess for differences among the treatment groups. Results: During the 21 days of observation after the procedure, all dogs recovered motor function and anal sphincter tone. With the exception of one dog... (Complete abstract, click electronic access below)

Submitted by ROBERTO BEZERRA Vital (roberto_vital@hotmail.com) on 2018-04-04T15:41:01Z No. of bitstreams: 1 Projeto v20.pdf: 3872313 bytes, checksum: d68e1cb15df36178f16f81f28f1b8bc8 (MD5) / Rejected by ROSANGELA APARECIDA LOBO null (rosangelalobo@btu.unesp.br), reason: Solicitamos que realize uma nova submissão seguindo as orientações abaixo: Necessário fazer as seguintes correções no arquivo submetido: problema 1: o arquivo submetido não contém capa, item obrigatório de acordo com as normas do seu programa Assim que tiver efetuado as correções submeta o arquivo em PDF novamente. Agradecemos a compreensão. on 2018-04-06T13:09:41Z (GMT) / Submitted by ROBERTO BEZERRA Vital (roberto_vital@hotmail.com) on 2018-04-10T22:23:33Z No. of bitstreams: 1 Roberto Vital (pós-defesa) com capa.pdf: 967175 bytes, checksum: c356f4d0b76b71e6f5e73e048a0fb341 (MD5) / Approved for entry into archive by ROSANGELA APARECIDA LOBO null (rosangelalobo@btu.unesp.br) on 2018-04-11T12:04:37Z (GMT) No. of bitstreams: 1 vital_rb_dr_bot.pdf: 967175 bytes, checksum: c356f4d0b76b71e6f5e73e048a0fb341 (MD5) / Made available in DSpace on 2018-04-11T12:04:37Z (GMT). No. of bitstreams: 1 vital_rb_dr_bot.pdf: 967175 bytes, checksum: c356f4d0b76b71e6f5e73e048a0fb341 (MD5) Previous issue date: 2018-03-01 / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / A espasticidade leva a perda na qualidade de vida, capacidade funcional do indivíduo e a alterações psicossociais. O baclofeno é fármaco relaxante muscular de ação central, utilizado no tratamento da espasticidade e é substância análoga ao ácido gama amino-butírico (GABA). Sua administração por via subaracnoidea permite que doses pequenas sejam utilizadas, minimizando efeitos adversos. A pesquisa consistiu em determinar os efeitos da administração de baclofeno em dose única, no espaço subaracnoideo de coelhos, sobre a medula espinal e as meninges. Foram utilizados coelhos, divididos em três grupos: G1, G2 e G3, com injeção no espaço subaracnoideo de soro fisiológico, baclofeno 100 μg e 200 μg respectivamente. Posteriormente foram realizadas as análises histológicas das meninges e medula dos coelhos. Os resultados da presente pesquisa mostram que o baclofeno, independe da dose administrada, causou lesão de tecido nervoso e de meninges em 20% (n=8) dos coelhos estudados. As alterações histológicas foram predominantemente observadas na região posterior das meninges. Podemos concluir que neste modelo experimental em coelhos o baclofeno desencadeou reação inflamatória no tecido nervoso e nas meninges. / Spasticity leads to a reduced quality of life, functional capacity limitations, and changes in the psychosocial well-being of an individual. Baclofen is a centrally acting muscle relaxant that is used in the treatment of spasticity and is an analog of gammaamino-butyric acid. Its administration via the subarachnoid route allows the use of small doses, thus minimizing adverse effects. The aim of the study was to determine the effects of administration of a single dose of baclofen into the subarachnoid space of rabbits, on the spinal cord and meninges. Methods: The rabbits were divided into three groups. The first group (G1) was injected with saline solution. The second and third groups (G2 and G3) received 100 and 200 μg of baclofen in the subarachnoid space, respectively. Histological analysis of the meninges and spinal cord in rabbits was subsequently performed. The present findings showed that baclofen, regardless of the administered dose, caused damage to the nerve tissue and meninges in 20% (n = 8) of the tested rabbits. The histological changes were predominantly observed in the posterior portion of the meninges. We conclude that, in this rabbit experimental model, baclofen caused an inflammatory reaction in the nervous tissue and meninges. / Fapesp 2011/ 22262-1

Orientador: Eliana Marisa Ganem / Banca: Yara Marcondes Machado Castiglia / Banca: Guilherme Antonio Moreira de Barros / Banca: Anita Leocádia de Matos / Banca: Angélica de Fátima de Assunção Braga / Resumo: A amitriptilina é o protótipo dos antidepressivos tricíclicos, classe de fármaco muito utilizada no tratamento da dor neuropática. Tem por propriedade principal a inibição da recaptação de serotonina e noradrenalina, além de interagir com diversos outros receptores. Estudos recentes demonstraram que os antidepressivos tricíclicos são potentes bloqueadores dos canais de sódio, potássio e cálcio, apresentando propriedades semelhantes aos anestésicos locais. Assim existe potencial para que esta classe farmacológica possa ser utilizada no neuroeixo como adjuvante anestésico local ou no tratamento de síndromes dolorosas neuropáticas refratárias. Entretanto, até o presente momento, não há consenso quanto a neurotoxicidade desta classe farmacológica sobre a medula e as meninges. O objetivo desta pesquisa foi avaliar a toxicidade da amitriptilina sobre a medula e as meninges quando administrada pela via subaracnóidea em cães. Método: Vinte e um animais foram randomizados em três grupos que receberam pela via subaracnóidea: Grupo 1 - Solução fisiológica 0,9%; Grupo 2 - solução de amitriptilina 5 mmol.ml-1; Grupo 3- solução de amitriptilina 10 mmol.ml-1. A punção subaracnóidea foi realizada no espaço intervertebral L6-L7. O volume da solução injetada foi de 1 ml. Os animais foram avaliados após uma hora da administração do fármaco e durante os 21 dias que permaneceram em cativeiro quanto ao tônus do esfíncter anal, bloqueio motor e sensibilidade dolorosa. Os animais foram sacrificados por eletrocussão sob anestesia. A medula e as meninges fixadas com solução de formalina 10%, coradas pelos métodos hematoxilina-eosina e tricrômico de Masson, para posterior analise histológica. O estudo foi duplamente encoberto. Para avaliação estatística foi utilizada a análise de variância. Resultados: Durante o período de observação de 21 dias os animais... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Amitriptyline is the prototype drug of the tricyclic antidepressants, which are commonly used as adjuvant medications in the treatment of neuropathic pain syndromes. It is an inhibitor of the reuptake of serotonin and norepinephrine, as well as a blocking agent for great number of receptors. Recent reports have demonstrated tricyclic antidepressants as potent blocking agents for voltage-dependent ionic Na+, K+ and Ca++ channels. Presenting a local anesthetic property. Hence there is a potential role for the intra-spinal use of amitriptyline as an adjuvant in neuroaxial anesthesia and in the treatment of refractory neuropathic pain. Nevertheless, to our knowledge there is no known information regarding the possible neural and meningeal effects of neuraxial amitriptyline administration. Therefore, we conducted a study to evaluate the neural and meningeal toxicities profiles of the intraspinal administration of amitriptyline to dogs. Methods: 21 Dogs were randomly selected for one of three groups: Group 1- 0,9% saline; Group 2- amitriptyline 5 mmol.ml-1 solution; Group 3- amitriptyline 10 mmol.ml-1 solution. In each of the groups one milliliter of the randomized solution was intraspinally administered by an investigator blinded for the intervention group. The dogs were evaluated one hour after awaking from the anesthesia and the following 21 days in the three following domains: anal sphincter tone, motor blockage and pain. The dogs were sacrificed by electrocution under anesthesia, the spinal cords were removed, fixed in 10% Formalin solution, stained by hematoxylin and eosin and Masson's trichrome technique for posterior histological analysis. We used analysis of variance to assess for differences among the treatment groups. Results: During the 21 days of observation after the procedure, all dogs recovered motor function and anal sphincter tone. With the exception of one dog... (Complete abstract, click electronic access below) / Doutor

nÃo hà / A vincristina à um quimioterÃpico e seu uso à limitado devido a neuropatia perifÃrica, com acometimento autonÃmico, sensitivo e motor. Sulfato de vincristina ou salina foram injetados na veia da cauda, nas doses de 50 Âg/Kg (5 doses), 100 Âg/Kg (2-5 doses) ou 150 Âg/Kg (1, 2 ou 5 doses) a cada dois dias em 144 ratos Wistar machos (200-250 g). No dia seguinte, os animais receberam a refeiÃÃo-teste por gavagem e foram sacrificados 10 minutos apÃs. A recuperaÃÃo gÃstrica e intestinal de corante foi determinada por espectrofotometria. ConstipaÃÃo foi avaliada pelo peso colÃnico e neuropatia sensitiva pela latÃncia tÃrmica (51Â0,5ÂC). PressÃo arterial mÃdia (PAM) e freqÃÃncia cardÃaca (FC) basais e valores da PAM e FC apÃs a administraÃÃo de fenilefrina 5 Âg/Kg e atropina 0,5 mg/Kg foram usados para estudo dos baroreflexos. DiferenÃas foram avaliadas por One-Way ANOVA com P<0,05. Tratamentos crÃnicos com 5 doses de 50 Âg/Kg; 3, 4 e 5 doses de 100 Âg/Kg; 2 e 5 doses de 150 Âg/Kg causaram retardo do esvaziamento gÃstrico (EG) (P<0,05). Duas e 5 doses de 150 Âg/kg induziram constipaÃÃo e houve reduÃÃo da latÃncia tÃrmica apÃs 1 dose de 50 Âg/Kg, 100 Âg/Kg e 150 Âg/kg (P<0,05). O efeito da vincristina sobre o EG nÃo foi evidenciado uma e duas semanas apÃs o tratamento com 5 doses de 150 Âg/Kg (P>0,05). Houve reduÃÃo do tempo de latÃncia ao calor por atà duas semanas apÃs 5 doses de 150 Âg/Kg (P<0,05). Vincristina potencializou a reduÃÃo da FC induzida pela fenilefrina e aumentou a resposta cardÃaca à atropina (P<0,05). A neuropatia autonÃmica induzida pela vincristina cursa com retardo do EG, alteraÃÃes na resposta baroreflexa e aumento do peso colÃnico. A neuropatia sensitiva precede o surgimento das alteraÃÃes autonÃmicas e persiste apÃs a reversÃo destas. / Vincristine is a chemotherapy drug and its use is limited by peripheral neuropathy with autonomic, sensory and motor involvement. Vincristine sulphate or saline was injected into the tail vein at doses of 50 Âg/Kg (5 doses), 100 Âg/Kg (2-5 doses) or 150 Âg/Kg (1, 2 or 5 doses) QOD in 144 male Wistar rats (200-250g). Next day, they were gavage-fed with a test meal and sacrificed 10 minutes later. Gastric and intestinal dye recovery was determined by spectrophotometry. Basal mean arterial pressure (MAP) and heart rate (HR) and peak values of MAP and HR after i.v. phenylephrine 5 Âg/Kg and atropine 0.5 mg/Kg were used to evaluate the baroreflex responses. Differences were evaluated by One-Way ANOVA with P<0.05. Chronic treatment with 5 doses of 50 Âg/Kg; 3, 4 and 5 doses of 100 Âg/Kg; 2 and 5 doses of 150 Âg/Kg delayed gastric emptying (GE) (P<0.05). Two and 5 doses of 150 Âg/Kg induced constipation and reduction in withdrawal latencies occurred after 1 dose of 50 Âg/Kg, 100 Âg/Kg and 150 Âg/Kg (P<0.05). Vincristine (150 Âg/Kg) immediately decreased fecal output (P<0.05). The effect of vincristine on the GE was not present in rats treated with 5 doses of vincristine 150 Âg/kg one week and two weeks after the last dose (P>0.05). The withdrawal latency decrease lasted for at least 2 weeks after 5 doses of 150 Âg/Kg (P<0.05). Vincristine enhanced the HR reduction induced by phenylephrine and enhanced cardiac response to atropine (P<0.05). Vincristine-induced autonomic neuropathy courses with delayed GE, altered baroreflex responses and increased colonic weight. Sensory neuropathy preceded and outlasted these autonomic changes.

Mefloquine hydrochloride is an antimalarial agent that has been used for the past 40 years. Numerous reports of neurological side effects have recently led the FDA to issue a strong warning regarding long-term neurological effects. This warning lead to the U.S. Army’s Special Forces and other components to discontinue its use in July of 2013. Despite reported adverse side effects, mefloquine remains in circulation and is recommended to travelers going to specific Asian countries. Mefloquine has been used as a treatment for those already infected with the malaria parasite (blood concentrations ranging from 2.1 to 23 µM), and as prophylaxis (blood concentrations averaging 3.8 µM) (Dow 2003). The purpose of this study was to quantify Mefloquine’s toxicity using spontaneously active nerve cell networks growing on microelectrode arrays in vitro and to identify compounds that alleviate or reduce toxic effects. The current literature on mefloquine toxicity is lacking electrophysiological data. These data will contribute to research on the mechanism of adverse side effects associated with mefloquine use. Sequential titration experiments were performed by adding increasing concentrations of mefloquine solution to cultured neurons. Network responses were quantified and reversibility was examined. In each network, activity decreases were normalized as a percent of reference activity yielding a mean IC50 value of 5.97 ± 0.44 (SD) µM (n=6). After total activity loss, no activity was recovered with two successive medium changes. To test for network response desensitization resulting from sequential applications over 5-6 hr periods, one-point titrations at varying concentrations were conducted with fresh networks. These experiments yielded a single concentration response curve with an IC50 value of 2.97 µM. This represents a statistically significant shift (p < 0.0001) to lower concentrations of mefloquine, demonstrating that sequential applications result in network desensitization. After mefloquine exposures, cells were evaluated for irreversible cytotoxic damage. Over a 12-hour period under 6 µM mefloquine, process beading and granulation of somal cytoplasm were observed. At 8 µM mefloquine cell stress was apparent after only 10 minutes with major glial damage and process beading at 120 minutes. In this study, quinolinic acid served as a neuroprotectant at 20 µM. There have been multiple studies on the endogenous concentrations of quinolinic acid and current literature is quite variable. Immunocompromised individuals have some of the highest blood levels of quinolinic acid (up to 20 µM). With 30 min pre-applications of quinolinic acid, the mefloquine IC50 value shifted from 5.97 ± 0.44 µM (n=6), to 9.28 ± 0.55 µM (n=3). This represents a statistically significant change to higher mefloquine concentrations and demonstrates neuroprotection.

Paracetamol is a widely used non-prescription analgesic and antipyretic. Despite its wide usage, the mechanism of action of paracetamol is not fully known. It has been found that paracetamol interacts with the central cyclooxygenase system which is likely responsible for its antipyreticeffect whereas the analgesic effect of paracetamol mainly depends on cannabinoid receptor type 1 activation. Paracetamol is considered the first choice for treatment of pain and/or fever during pregnancy and can reach the developing brain following consumption since it crosses both blood-brain and placental barriers. However, increasing evidence from both animal and human studies show that developmental paracetamol exposure is associated with adverse behavioural outcomes later in life. Nonetheless, the mechanism behind paracetamol neurotoxicity is still unknown. The main aim of this study was to investigate whether adult mice neonatally exposed to paracetamol during a critical period of brain development known as brain growth spurt havealtered expression of biomarkers important for brain development. Mice were exposed to either paracetamol (30 + 30 mg / kg, 4-hour interval) or saline on postnatal day 10. The mice's brains were then dissected out when they were two months old. In this study, the brains were cryosectioned and examined by immunohistochemistry. This study shows that there is no significant difference in the protein levels of synaptophysin (SYP), a marker for synaptic density, in Cornu Ammonis subfield 3 (also known as CA3), Cornu Ammonis subfield 1 (also known as CA1), and dentate gyrus (DG) regions of adult hippocampus between paracetamol treated mice and controls. These findings suggest that previously observed adult behavioural changes after neonatal exposure to paracetamol may have other origins than effects on synaptic density using SYP marker. Further research on possible mechanisms behind paracetamol-induced adverse developmental effects is needed.

The characteristics feature of neurotoxicity is a definable lesion which can account for observed deficits, corresponding to loss of nuclei or axonal fibers normally comprising a specific pathway or tract. However, with ontogenetic lesions, the operative definition fails. In rats lesioned as neonates with 6-hydroxydopamine (6-OHDA), near-total destruction of dopamine-(DA-) containing nerves is produced, and this itself is definable. However, the most prominent feature of rats so-lesioned is the DA receptor supersensitivity (DARSS) that develops and then persists throughtout the lifespan. DA D1 receptors show overt supersensitivity to agonists producing vacuous chewing movements (VCMs), while D1 receptors associated with locomotor activity have a latent supersensitivity that must be unmasked by repeated D1 or D2 agonist treatments - a 'priming' phenomenon. This D1 DARSS is not usually associated in either a change in D1 receptor number (Bmax) or affinity (Kd). In contrast to D1 DARSS, D2 receptors are not so predictably supersensitized by a lession of DA neurons. In reality, the permanently exaggerated response to an agonist by supersensitized receptors is per se a manifestation of neurotoxicity. Despite dramatic behavioral responses mediated by supersensitized receptors, DARSS has not been easy to correlate with enhanced production of second messengers or early response genes. Altered signaling (i.e., neuronal cross-talk) in defined pathways may represent the mechanism that produces so-called receptor supersensitization. Longlived agonist-induced behavioral abnormality, with or without anatomic evidence of a neuronal lesion, is one of the products of DA D1 receptor supersensitization - it self an index of neurotoxicity.

Local anesthetics (LAs) are necessary for the regional anesthesia, spinal anesthesia, and pain management. However, the application of LAs may cause neurotoxicity and result in postoperative neurological complications. Lithium is a mood stabilizer for the treatment of bipolar disorder and may exert neuroprotective effects. In this study, we evaluated the effects of lithium on bupivacaine (a frequently used LAs)-induced injury in mouse neuroblastoma neuro 2a (N2a) cells. N2a cells were treated with bupivacaine in the presence or absence of lithium. After treatment, the cell injury was evaluated by examination of viability, morphology changes, and nuclear condensation. The levels of mitochondrial transmembrane potential (δψm) and activation of phosphatidylinositol-3-kinase (PI3K)/ threonine-serine protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) were also examined. In a separate experiment, we investigated the effect of Akt and ERK inhibition on cell injury after bupivacaine and lithium treatment. Pretreatment of N2a cells with lithium significantly attenuated bupivacaine-induced cell injury. Lithium pretreatment completely reversed the suppression of PI3K/Akt and ERK signalings and significantly prevented the decline of δψ m in N2a cells after bupivacaine treatment. More importantly, pharmacological inhibition of Akt and ERK diminished the protective effect of lithium against bupivacaine-induced neuronal death. Our data suggest that lithium pretreatment provides a protective effect on bupivacaine-induced neuronal cell injury. This action of lithium is mediated through, at least in part, the activating of PI3K/Akt- and ERK-dependent mechanisms. Because lithium is a clinically proved safety drug for neurons, it is worthwhile to identify whether coadministration of LAs with lithium will decrease the risks of LAs-induced postoperative neurological complications in clinic practice.

Indiana University-Purdue University Indianapolis (IUPUI) / The main focus of this study is to determine the impact of Set-Binding Factor 2 (SBF2) on human-derived neurons in the context of taxane-induced peripheral neuropathy. Taxane-induced peripheral neuropathy (TIPN) is a devastating survivorship issue for many cancer patients; SBF2 has been previously identified as a potential germline predictor that has been found to be significantly associated with severe TIPN in African American (AA) patients. The work described here provides ex vivo support for the use of SBF2 as a genotypic biomarker to identify a priori which patients are at a higher risk of manifesting severe TIPN. This study demonstrates that diminished expression of SBF2 exacerbated the effect of paclitaxel on viability and morphology and altered the functional response of a neuronal model exposed to paclitaxel treatment. Furthermore, transcriptomic work showed that reduced expression of SBF2 in a neuronal model treated with paclitaxel impacted the expression of genes that modulate stress-induced cell death and pain threshold. Altogether, these findings suggest that SBF2 plays a role in the development of TIPN. This work sheds light on the pathways potentially involving SBF2 that can be studied to further evaluate the function of this gene in neurons and its contribution to severe TIPN. Further functional approaches investigating these pathways will be pivotal in elucidating the underlying biological mechanism for this toxicity and identifying novel targeted therapeutic strategies to prevent or treat TIPN. / 2021-05-17