Intravenous administration of recombinant Phα1ß: Antinociceptive properties and morphine tolerance reversal in a cancer-associated pain model.

Cancer-related pain is considered one of the most prevalent symptoms for those affected by cancer, significantly influencing quality of life and treatment outcomes. Morphine is currently employed for analgesic treatment in this case, however, chronic use of this opioid is limited by the development of analgesic tolerance and adverse effects, such as digestive and neurological disorders. Alternative therapies, such as ion channel blockade, are explored. The toxin Phα1ß has demonstrated efficacy in blocking calcium channels, making it a potential candidate for alleviating cancer-related pain. This study aims to assess the antinociceptive effects resulting from intravenous administration of the recombinant form of Phα1ß (r-Phα1ß) in an experimental model of cancer-related pain in mice, tolerant or not to morphine. The model of cancer-induced pain was used to evaluate these effects, with the injection of B16F10 cells, followed by the administration of the r-Phα1ß, and evaluation of the mechanical threshold by the von Frey test. Also, adverse effects were assessed using a score scale, the rotarod, and open field tests. Results indicate that the administration of r-Phα1ß provoked antinociception in animals with cancer-induced mechanical hyperalgesia, with or without morphine tolerance. Previous administration of r-Phα1ß was able to recover the analgesic activity of morphine in animals tolerant to this opioid. r-Phα1ß was proved safe for these parameters, as no adverse effects related to motor and behavioral activity were observed following intravenous administration. This study suggests that the concomitant use of morphine and r-Phα1ß could be a viable strategy for pain modulation in cancer patients.

Ketamine treatment protects against oxidative damage and the immunological response induced by electroconvulsive therapy.

BACKGROUND: Electroconvulsive therapy (ECT) is often recommended for major depressive disorder (MDD) for those who do not respond to the first and second antidepressant trials. A combination of two therapies could improve antidepressant efficacy. Thus, this study aimed to investigate the synergistic effects of ECT combined to antidepressants with a different mechanism of action. METHODS: Rats were treated once a day, for five days with ketamine (5 mg/kg), fluoxetine (1 mg/kg), and bupropion (4 mg/kg) alone or in combination with ECT (1 mA; 100 V). After, oxidative damage and antioxidant capacity were assessed in the prefrontal cortex (PFC) and hippocampus, and pro-inflammatory cytokines levels were evaluated in the serum. RESULTS: ECT alone increased lipid peroxidation in the PFC and hippocampus. In the PFC of rats treated with ECT in combination with fluoxetine and bupropion, and in the hippocampus of rats treated with ECT combined with ketamine and bupropion there was a reduction in the lipid peroxidation. The nitrite/nitrate was increased by ECT alone but reverted by combination with ketamine in the hippocampus. Superoxide dismutase (SOD) was increased by ECT and maintained by fluoxetine and bupropion in the PFC. ECT alone increased interleukin-1ß (IL-1ß) and the administration of ketamine was able to revert this increase showing a neuroprotective effect of this drug when in combination with ECT. CONCLUSION: The treatment with ECT leads to an increase in oxidative damage and alters the immunological system. The combination with ketamine was able to protect against oxidative damage and the immunological response induced by ECT.

Strategies for Treatment-Resistant Depression: Lessons Learned from Animal Models.

Around 300 million individuals are affected by major depressive disorder (MDD) in the world. Despite this high number of affected individuals, more than 50% of patients do not respond to antidepressants approved to treat MDD. Patients with MDD that do not respond to 2 or more first-line antidepressant treatments are considered to have treatment-resistant depression (TRD). Animal models of depression are important tools to better understand the pathophysiology of MDD as well as to help in the development of novel and fast antidepressants for TRD patients. This review will emphasize some discovery strategies for TRD from studies on animal models, including, antagonists of N-methyl-D-aspartate (NMDA) receptor (ketamine and memantine), electroconvulsive therapy (ECT), lithium, minocycline, quetiapine, and deep brain stimulation. Animal models of depression are not sufficient to represent all the traits of TRD, but they greatly aid in understanding the mechanism by which therapies that work for TRD exert antidepressant effects. Interestingly, these innovative therapies have mechanisms of action different from those of classic antidepressants. These effects are mainly related to the regulation of neurotransmitter activity, including general glutamate and increased connectivity, synaptic capacity, and neuroplasticity.

LC/QTOF profile and preliminary stability studies of an enriched flavonoid fraction of Cecropia pachystachya Trécul leaves with potential antidepressant-like activity.

There is increasing interest in natural antioxidants that are candidates for the prevention of brain damage occurring in major depressive disorders. Cecropia pachystachya is a tropical tree species of Central and South America and a rich source of polyphenols, particularly flavonoids. The aim of this study was to characterize the flavonoid profile of an enriched flavonoid fraction of C. pachystachya (EFF-Cp) and evaluate the antidepressant-like effects of its acute administration in behavior, cytokine levels, oxidative stress and energy metabolism parameters. The EFF-Cp chemical characterization was performed by HPLC/DAD and LC/QTOF. The antidepressant-like effects were performed by the forced swimming test, splash test and open field test. EFF-Cp revealed 15 flavonoids, including seven new glycosyl flavonoids for C. pachystachya. Quantitatively, EFF-Cp showed isoorientin (43.46 mg/g), orientin (23.42 mg/g) and isovitexin (17.45 mg/g) as major C-glycosyl flavonoids. In addition, EFF-Cp at doses 50 and 100 mg/kg reduced the immobility time in the forced swimming test, without changing the locomotor activity and grooming time. In addition, EFF-Cp was able to prevent the oxidative damage in some brain areas. In conclusion, the results of this study suggest that EFF-Cp exerts antidepressant-like effects with its antioxidant properties.

Depressive disorders and comorbidities among the elderly: a population-based study / Transtornos depressivos e algumas comorbidades em idosos: um estudo de base populacional

Objective The present study assessed the prevalence of depressive disorders and associated factors in a sample of elderly persons in the south of Santa Catarina. Methods A cross-sectional study based on population data was performed, evaluating 1021 elderly individuals aged between 60 and 79 years. Home interviews were carried out using the Portuguese version of the Mini International Neuropsychiatric Interview (MINI), in order to collect demographic data, information on hypertension and reports of acute myocardial infarction. The disorders studied were current depressive episode, dysthymia and a comorbidity of a depressive episode and dysthymia, representing double depression. The comparison of mean age and prevalence was made with the t-test and other associations were analyzed using the Chi-squared test. Results The prevalence of depression was 26.2%, while 5.5% of the sample suffered from dysthymia and 2.7% experienced double depression. Risk factors for depression were: nine or more years of schooling [PR = 1.44 (1.17 to 1.77); p <0.05] and being a current smoker [OR = 1.63 (1.30-2.05); p <0.05]. Dysthymia was associated with the male gender [OR = 6.46 (3.29 to 12.64); p <0.05], reports of hypertension [OR = 2.55 (1.53 to 4.24); p <0.05] and being either a current [OR = 1.86 (1.02 to 3.42); p <0.05] or past or former [OR = 2.89 (1.48 to 5.65); p <0.05] smoker. The same risk factors as for dysthymia were found for double depression: male [OR = 4.21 (1.80 to 9.81); p <0.05], reports of hypertension [OR = 8.11 (3.32 to 19.80); p <0.05], and being either a current [OR = 5.72 (1.64 to 19.93); p <0.05] or past [PR = 13.11 (3.75 to 45.86); p <0.05] smoker. Conclusions The present study shows that depressive disorders are a common phenomenon among the elderly. The results not only corroborated with other studies, but found slightly higher levels of depressive disorders among the elderly population.

Objetivo Avaliar a prevalência de transtornos depressivos e fatores associados em uma amostra de idosos no Sul de Santa Catarina. Método Estudo transversal com base de dados populacional, que avaliou 1.021 indivíduos idosos entre 60 e 79 anos. Foram realizadas entrevistas domiciliares com a versão em português do Mini International Neuropsychiatric Interview (MINI), coleta de dados sociodemográficos, informações sobre hipertensão arterial sistêmica, infarto agudo do miocárdio e tabagismo. Os transtornos estudados foram episódio depressivo atual, distimia e comorbidade entre episódio depressivo e distimia, caracterizando depressão dupla. A comparação das médias de idade e prevalências foi feita com o teste t Student, as demais associações foram analisadas pelo teste Qui-quadrado. Resultados A prevalência de depressão foi de 26,2%; distimia, 5,5%; e depressão dupla, 2,7%. Fatores de risco para depressão: nove anos ou mais de estudo [RP=1,44(1,17-1,77); p<0,05] e tabagismo atual [RP=1,63(1,30-2,05); p<0,05]. A distimia foi associada ao gênero masculino [RP=6,46(3,29-12,64); p<0,05], relato de hipertensão arterial [RP=2,55(1,53-4,24);p<0,05] e tabagismo, tanto atual [RP=1,86(1,02-3,42),p<0,05] quanto passado ou ex-tabagistas [RP=2,89(1,48-5,65); p<0,05]. Para a depressão dupla, repetiram os mesmos fatores de risco da distimia: gênero masculino [RP=4,21(1,80-9,81); p<0,05], relato de hipertensão arterial [RP=8,11(3,32-19,80); p<0,05], tabagismo atual [RP=5,72(1,64-19,93); p<0,05] e passado [RP=13,11(3,75-45,86); p<0,05]. Conclusão Os dados demonstram que quadros depressivos são fenômenos frequentes e atingem um percentual significativo de idosos. Adicionalmente, os transtornos depressivos foram associados a fatores sociodemográficos e doenças crônicas, como nível de escolaridade, tabagismo e hipertensão arterial.

Antioxidant Therapy Alters Brain MAPK-JNK and BDNF Signaling Path-ways in Experimental Diabetes Mellitus.

This study was designed to investigate the effects of treatment with the antioxidants N-acetylcysteine (NAC) and deferoxamine (DFX) in intracellular pathways in the brain of diabetic rats. To conduct this study we induced diabetes in Wistar rats with a single injection of alloxan, and afterwards rats were treated with NAC or DFX for 14 days. Following treatment completion, the immunocontent of c-Jun N-terminal kinase (JNK), mitogen-activated protein kinase-38 (MAPK38), brain-derived neurotrophic factor (BDNF), and protein kinases A and C (PKA and PKC) were determined in the prefrontal cortex (PFC), hippocampus, amygdala and nucleus accumbens (NAc). DFX treatment increased JNK content in the PFC and NAc of diabetic rats. In the amygdala, JNK was increased in diabetics treated with saline or NAC. MAPK38 was decreased in the PFC of control and in diabetic rats treated with NAC or DFX; and in the NAc in all groups. PKA was decreased in the PFC with DFX treatment. In the amygdala, PKA content was increased in diabetic rats treated with either saline or NAC, compared to controls; and it was decreased in either NAC or DFX-treated groups, compared to saline-treated diabetic animals. In the NAc, PKA was increased in NAC-treated diabetic rats. PKC was increased in the amygdala of NAC-treated diabetic rats. In the PFC, the BDNF levels were decreased following treatment with DFX in diabetic rats. In the hippocampus of diabetic rats the BDNF levels were decreased. However, treatment with DFX reversed this effect. In the amygdala the BDNF increased with DFX in non-diabetic rats. In the NAc DFX treatment increased the BDNF levels in diabetic rats. In conclusion, both diabetes and treatment with antioxidants were able to alter intracellular pathways involved in the regulation of cell survival in a brain area and treatment-dependent fashion.

ß-Carboline harmine reverses the effects induced by stress on behaviour and citrate synthase activity in the rat prefrontal cortex.

OBJECTIVES: The present study was aimed at evaluating the effects of the administration of ß-carboline harmine on behaviour and citrate synthase activity in the brain of rats exposed to chronic mild stress (CMS) procedure. METHODS: To this aim, after 40 days of exposure to CMS procedure, rats were treated with harmine (15 mg/kg/day) for 7 days, then memory, anhedonia and citrate synthase activity were assessed. Result Our findings demonstrated that stressed rats treated with saline increased the sucrose intake, and the stressed rats treated with harmine reversed this effect. Neither stress nor harmine treatment altered memory performance in rats. In addition, chronic stressful situations induced increase in citrate synthase activity in the prefrontal cortex, but not in the hippocampus and striatum. Treatment with harmine reversed the increase in citrate synthase activity in the prefrontal cortex. CONCLUSION: These findings support the hypothesis that harmine could be involved in controlling the energy metabolism.