Cognitive impairment and elevated peripheral cytokines in breast cancer patients receiving chemotherapy.

BACKGROUND: Anthracyclines-based regimen (5-fluorouracil, doxorubicin, and cyclophosphamide (FAC); cyclophosphamide, epirubicin, and 5-fluorouracil [CEF]) and non-anthracycline based regimens (cyclophosphamide, methotrexate, and 5-fluorouracil [CMF]) are widely used as neoadjuvant chemotherapy for breast cancer patients. OBJECTIVE: The present study was conducted to observe the effects of FAC, CEF, and CMF regimen on cognition and circulatory proinflammatory cytokines (interleukin 6 [IL-6] and interleukin 1ß [IL-1ß]) for the duration of three cycles of chemotherapy in breast cancer patients. METHODS: Eighty newly diagnosed HER-2 negative breast cancer patients were enrolled and divided into 3 groups as FAC- (n = 27), CEF- (n = 26), and CMF- (n = 27) receiving patients. Serum IL-6 and IL-1ß levels were measured by using enzyme-linked immunosorbent assay (ELISA), and cognition was assessed using the Mini-Mental State examination (MMSE) questionnaire. RESULTS: Anthracycline-based regimen was found to increase the levels of IL-6, IL-1ß, and decreased MMSE scores compared with CMF regimen (p < 0.05). CONCLUSION: Anthracycline-based regimen caused comparatively higher peripheral inflammation, which could be the reason for more decline in cognition in anthracycline-receiving patients than non-anthracycline group.

ANTECEDENTES: Regime baseado em antraciclinas (5-fluorouracil, doxorrubicina e ciclofosfamida [FAC]; ciclofosfamida, epirrubicina e 5-fluorouracil [CEF]) e regimes não baseados em antraciclina (ciclofosfamida, metotrexato e 5-fluorouracil (CMF]) são amplamente utilizados como quimioterapia neoadjuvante para pacientes com câncer de mama. OBJETIVO: O presente estudo foi realizado para observar os efeitos do regime FAC, CEF e CMF na cognição e citocinas pró-inflamatórias circulatórias (interleucina 6 [IL-6] e interleucina 1ß [IL-1ß]) durante três ciclos de quimioterapia em pacientes com câncer de mama. MéTODOS: Oitenta pacientes recém-diagnosticadas com câncer de mama HER-2 negativo foram recrutadas e divididas em 3 grupos de pacientes que receberam FAC (n = 27), CEF (n = 26) ou CMF (n = 27). Os níveis séricos de IL-6 e IL-1ß foram medidos por enzyme-linked immunosorbent assay (ELISA) e a cognição foi avaliada por meio do questionário Mini-Mental State Examination (MMSE). RESULTADOS: O regime baseado em antraciclinas aumentou os níveis de IL-6, IL-1ß e diminuiu os escores do MMSE em comparação com o regime CMF (p < 0,05). CONCLUSãO: O regime baseado em antraciclinas causou inflamação periférica comparativamente mais alta, o que pode ser a razão para maior declínio na cognição em pacientes que receberam antraciclinas do que no grupo que não recebeu antraciclina.

Cognitive impairment and elevated peripheral cytokines in breast cancer patients receiving chemotherapy / Comprometimento cognitivo e citocinas periféricas elevadas em pacientes com câncer de mama recebendo quimioterapia

Abstract Background Anthracyclines-based regimen (5-fluorouracil, doxorubicin, and cyclophosphamide (FAC); cyclophosphamide, epirubicin, and 5-fluorouracil [CEF]) and non-anthracycline based regimens (cyclophosphamide, methotrexate, and 5-fluorouracil [CMF]) are widely used as neoadjuvant chemotherapy for breast cancer patients. Objective The present study was conducted to observe the effects of FAC, CEF, and CMF regimen on cognition and circulatory proinflammatory cytokines (interleukin 6 [IL-6] and interleukin 1β [IL-1β]) for the duration of three cycles of chemotherapy in breast cancer patients. Methods Eighty newly diagnosed HER-2 negative breast cancer patients were enrolled and divided into 3 groups as FAC- (n= 27), CEF- (n= 26), and CMF- (n= 27) receiving patients. Serum IL-6 and IL-1β levels were measured by using enzyme-linked immunosorbent assay (ELISA), and cognition was assessed using the Mini-Mental State examination (MMSE) questionnaire. Results Anthracycline-based regimen was found to increase the levels of IL-6, IL-1β, and decreased MMSE scores compared with CMF regimen (p< 0.05). Conclusion Anthracycline-based regimen caused comparatively higher peripheral inflammation, which could be the reason for more decline in cognition in anthracycline-receiving patients than non-anthracycline group.

Resumo Antecedentes Regime baseado em antraciclinas (5-fluorouracil, doxorrubicina e ciclofosfamida [FAC]; ciclofosfamida, epirrubicina e 5-fluorouracil [CEF]) e regimes não baseados em antraciclina (ciclofosfamida, metotrexato e 5-fluorouracil (CMF]) são amplamente utilizados como quimioterapia neoadjuvante para pacientes com câncer de mama. Objetivo O presente estudo foi realizado para observar os efeitos do regime FAC, CEF e CMF na cognição e citocinas pró-inflamatórias circulatórias (interleucina 6 [IL-6] e interleucina 1β [IL-1β]) durante três ciclos de quimioterapia em pacientes com câncer de mama. Métodos Oitenta pacientes recém-diagnosticadas com câncer de mama HER-2 negativo foram recrutadas e divididas em 3 grupos de pacientes que receberam FAC (n= 27), CEF (n= 26) ou CMF (n= 27). Os níveis séricos de IL-6 e IL-1β foram medidos por enzyme-linked immunosorbent assay (ELISA) e a cognição foi avaliada por meio do questionário Mini-Mental State Examination (MMSE). Resultados O regime baseado em antraciclinas aumentou os níveis de IL-6, IL-1β e diminuiu os escores do MMSE em comparação com o regime CMF (p< 0,05). Conclusão O regime baseado em antraciclinas causou inflamação periférica comparativamente mais alta, o que pode ser a razão para maior declínio na cognição em pacientes que receberam antraciclinas do que no grupo que não recebeu antraciclina.

Resveratrol-Loaded Glutathione-Coated Collagen Nanoparticles Attenuate Acute Seizures by Inhibiting HMGB1 and TLR-4 in the Hippocampus of Mice.

Epilepsy is a relatively complicated neurological disorder that results in seizures. The use of resveratrol in treating seizures has been reported in recent studies. However, the low bioavailability of resveratrol and the difficulty of reaching the targeted location in the brain reduce its efficacy considerably. The side effects due to the higher concentration of drugs are another matter of concern. The purpose of the present study is to enhance the antiepileptic potential of resveratrol by delivering it to the brain's targeted location by encapsulating it in glutathione-coated collagen nanoparticles. The collagen nanoparticles increase the bioavailability of resveratrol, while the transport of resveratrol to its target location in the brain is facilitated by glutathione. By encapsulating resveratrol in glutathione-coated collagen nanoparticles, the concentration also substantially decreases. Resveratrol encapsulated in synthesized nanoparticles is referred to as nanoresveratrol. In the present study, nanoresveratrol effectiveness was studied through PTZ-induced seizures (PTZ-IS) and the increasing current electroshock (ICES) test. The efficacy of nanoresveratrol was further established using biochemical analysis, histopathological examinations, ELISA and real-time-PCR tests, and immunohistochemistry examination of the hippocampus of mice. Hence, this study is unique in the sense that it synthesized nanoresveratrol by using glutathione-coated collagen nanoparticles, followed by its application to treating seizures. On the basis of the study results, nanoresveratrol was found to be effective in preventing cognitive impairment in the mice and controlling epilepsy seizures to a greater extent than resveratrol. The proposed nanoformulation also reduces the concentration of resveratrol considerably. The present study results show that even 0.4 mg/kg of nanoresveratrol outperforms 40 mg/kg of resveratrol.

Embelin ameliorates cognitive dysfunction and progression of kindling in pentylenetetrazol-induced kindling in mice by attenuating brain inflammation.

OBJECTIVE: This study was conducted to evaluate the effect of embelin (EMB) on various epileptic models and related brain inflammation. METHODS: Male Swiss albino mice were administered EMB (5, 10, and 20 mg/kg/p.o.) in acute and chronic study for 7 days and 35 days, respectively. Acute study included increasing current electroshock (ICES) and pentylenetetrazol (PTZ)-induced seizure test. Step-down latency (SDL) and forced swim test (FST) were performed to evaluate cognitive functions and depression-like behavior, respectively. Chronic study included PTZ-induced kindling. Levels of inflammatory biomarkers, namely interleukin-1 beta (IL-1ß), interleukin-1 receptor antagonist (IL-1Ra), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), were estimated in the hippocampus and cortex of the kindled brains by ELISA technique. Further, neurotransmitters (NTs), namely gamma aminobutyric acid (GABA), glutamate, and dopamine, were estimated by using validated liquid chromatography-mass spectrometry (LC-MS) method followed by ultra-high-performance liquid chromatography (UHPLC). RESULTS: Embelin (EMB) treatment increased the seizure threshold to hind limb extension (HLE) in the ICES test and decreased the seizure scores in the kindling experiment. Significantly low levels of IL-1ß, IL-1Ra, IL-6, and TNF-α were observed in the hippocampus of PTZ + EMB (10 and 20 mg/kg)-treated groups compared with PTZ+ vehicle-treated group. Significantly lower levels of IL-1Ra, IL-6, and TNF-α compared with PTZ+ vehicle-treated group were observed in the cortex of PTZ + EMB (10 and 20 mg/kg)-treated groups, while IL-1ß levels were found to be significantly lower only in the cortex of PTZ + EMB (20 mg/kg)-treated group. Increased levels of dopamine and GABA and decreased levels of glutamate in both hippocampus and cortex were observed in EMB + PTZ-treated groups compared with vehicle + PTZ-treated group. Latency of step down was found to be increased and immobility time in FST was decreased in EMB + PTZ groups compared with vehicle + PTZ group. CONCLUSION: Embelin suppressed epileptogenesis in the kindled mice via neurochemical modulation of neurotransmitters and inhibiting the inflammatory pathway. Further, EMB was also observed to be protecting the kindled animals from cognition and depression-like behavior.

Resveratrol suppressed seizures by attenuating IL-1ß, IL1-Ra, IL-6, and TNF-α in the hippocampus and cortex of kindled mice.

OBJECTIVE: There is an urge to identify new molecules which can modulate process of epileptogenesis, since currently available drugs act symptomatically and one-third of the patients remain refractory to the disease. Hence, the present study was conducted to evaluate the effects of Resveratrol (RESV) on epileptogenesis in pentylenetetrazole (PTZ)-induced kindling in mice. METHOD: Swiss albino mice were administered RESV (10, 20 and 40 mg/kg,p.o) in acute study. On the seventh day animals were subjected to various neurological and neurobehavioral tests viz, Increasing Current Electroshock Test (ICES), PTZ-induced seizures, passive avoidance response, and elevated plus maze test. For the development of kindling PTZ was administered in a dose of 25 mg/kg, i.p. on every alternate day and RESV in all the three doses was administered daily. Seizure score was continuously monitored till the development of kindling and cognition tests were performed in the end of the study. The animals were sacrificed and levels of inflammatory biomarkers viz., IL-1ß, interleukin-1 receptor antagonist (IL1-Ra), IL-6, and TNF-α were assessed in the hippocampus and cortex of the kindled animals. RESULTS: RESV in all three doses increased the seizure threshold to hind limb extension in the ICES test. RESV in all the tested doses suppressed the development of kindling and reduced the levels of IL-1ß, IL1-Ra, IL-6, and TNF-α in kindled mice. CONCLUSION: RESV suppressed the development of kindling in mice and decreased the levels of inflammatory biomarkers in their hippocampus. RESV modified brain inflammation during epileptogenesis and found to possess nootropic activity in the kindled mice.