RESUMO
BACKGROUND: We explored the relationship between symptoms, cognitive performance, neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR) (three markers of inflammation), and antipsychotic dose (in chlorpromazine units) in male and female patients with schizophrenia. METHODS: We conducted a cross-sectional analysis in patients with schizophrenia of the complete blood count and the results of neuropsychological testing, using the Welch t-test to compare groups and the Pearson test for correlations. RESULTS: We found that the NLR and the PLR are higher among women with schizophrenia when compared with men. In women, the NLR and the PLR correlate positively with antipsychotic drug dose and inversely with a working memory test (Direct Digit Span). Higher doses of antipsychotics are associated with worse working and semantic memory and mental flexibility in the women in our sample. CONCLUSION: Higher doses of antipsychotics were associated with worse working and semantic memory and mental flexibility in women with schizophrenia. No such correlations were present in men, suggesting that, in female patients, cognitive performance deteriorates as the antipsychotic dose is increased, a finding that could be mediated by inflammatory mechanisms, given the demonstrated relationship to biomarkers of inflammation - e.g., the NLR and the PLR. TRIAL REGISTRATION: NCT03788759 (ClinicalTrials.gov).
Assuntos
Antipsicóticos , Esquizofrenia , Feminino , Humanos , Masculino , Antipsicóticos/uso terapêutico , Cognição , Estudos Transversais , Inflamação , Linfócitos , Neutrófilos , Esquizofrenia/tratamento farmacológicoRESUMO
Schizophrenia is a mental disorder with sex bias in disease onset and symptom severity. Recently, it was observed that females present more severe symptoms in the perimenstrual phase of the menstrual cycle. The administration of estrogen also alleviates schizophrenia symptoms. Despite this, little is known about symptom fluctuation over the menstrual cycle and the underlying mechanisms. To address this issue, we worked with the two-hit schizophrenia animal model induced by neonatal exposure to a virus-like particle, Poly I:C, associated with peripubertal unpredictable stress exposure. Prepulse inhibition of the startle reflex (PPI) in male and female mice was considered analogous to human schizophrenia-like behavior. Female mice were studied in the proestrus (high-estrogen estrous cycle phase) and diestrus (low-estrogen phase). Additionally, we evaluated the hippocampal mRNA expression of estrogen synthesis proteins; TSPO and aromatase; and estrogen receptors ERα, ERß, and GPER. We also collected peripheral blood mononuclear cells (PBMCs) from male and female patients with schizophrenia and converted them to induced microglia-like cells (iMGs) to evaluate the expression of GPER. We observed raised hippocampal expression of GPER in two-hit female mice at the proestrus phase without PPI deficits and higher levels of proteins related to estrogen synthesis, TSPO, and aromatase. In contrast, two-hit adult males with PPI deficits presented lower hippocampal mRNA expression of TSPO, aromatase, and GPER. iMGs from male and female patients with schizophrenia showed lower mRNA expression of GPER than controls. Therefore, our results suggest that GPER alterations constitute an underlying mechanism for sex influence in schizophrenia.
Assuntos
Receptores de Estrogênio , Esquizofrenia , Adulto , Humanos , Masculino , Feminino , Animais , Camundongos , Receptores de Estrogênio/metabolismo , Receptor alfa de Estrogênio/metabolismo , Aromatase/metabolismo , Leucócitos Mononucleares/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Estrogênios/farmacologia , RNA Mensageiro , Proteínas de Ligação ao GTP/metabolismo , Receptores de GABA/metabolismoRESUMO
BACKGROUND: Schizophrenia (SCZ) is a neurodevelopmental disorder influenced by patient sex. Mechanisms underlying sex differences in SCZ remain unknown. A two-hit model of SCZ combines the exposure to perinatal infection (first-hit) with peripubertal unpredictable stress (PUS, second-hit). N-acetylcysteine (NAC) has been tested in SCZ because of the involvement of glutathione mechanisms in its neurobiology. AIMS: We aim to investigate whether NAC administration to peripubertal rats of both sexes could prevent behavioral and neurochemical changes induced by the two-hit model. METHODS: Wistar rats were exposed to polyinosinic:polycytidylic acid (a viral mimetic) or saline on postnatal days (PND) 5-7. On PND30-59 they received saline or NAC 220 mg/kg and between PND40-48 were subjected to PUS or left undisturbed. On PND60 behavioral and oxidative alterations were evaluated in the prefrontal cortex (PFC) and striatum. Mechanisms of hippocampal memory regulation such as immune expression of G protein-coupled estrogen receptor 1 (GPER), α7-nAChR and parvalbumin were also evaluated. RESULTS: NAC prevented sensorimotor gating deficits only in females, while it prevented alterations in social interaction, working memory and locomotor activity in both sexes. Again, in rats of both sexes, NAC prevented the following neurochemical alterations: glutathione (GSH) and nitrite levels in the PFC and lipid peroxidation in the PFC and striatum. Striatal oxidative alterations in GSH and nitrite were observed in females and prevented by NAC. Two-hit induced hippocampal alterations in females, namely expression of GPER-1, α7-nAChR and parvalbumin, were prevented by NAC. CONCLUSION: Our results highlights the influences of sex in NAC preventive effects in rats exposed to a two-hit schizophrenia model.
Assuntos
Acetilcisteína/farmacologia , Esquizofrenia/prevenção & controle , Caracteres Sexuais , Fatores Etários , Animais , Corpo Estriado/metabolismo , Feminino , Glutationa/metabolismo , Hipocampo/metabolismo , Peroxidação de Lipídeos , Locomoção/efeitos dos fármacos , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Nitritos/metabolismo , Parvalbuminas/biossíntese , Poli I-C , Córtex Pré-Frontal/metabolismo , Ratos , Receptores Acoplados a Proteínas G/biossíntese , Esquizofrenia/induzido quimicamente , Esquizofrenia/complicações , Filtro Sensorial/efeitos dos fármacos , Interação Social/efeitos dos fármacos , Estresse Psicológico/complicações , Receptor Nicotínico de Acetilcolina alfa7/biossínteseRESUMO
Neonatal N-methyl-D-aspartate (NMDA) receptor blockade in rodents triggers schizophrenia (SCZ)-like alterations during adult life. SCZ is influenced by gender in age of onset, premorbid functioning, and course. Estrogen, the hormone potentially driving the gender differences in SCZ, is known to present neuroprotective effects such as regulate oxidative pathways and the expression of brain-derived neurotrophic factor (BDNF). Thus, the aim of this study was to verify if differences in gender and/or estrous cycle phase during adulthood would influence the development of behavioral and neurochemical alterations in animals neonatally administered ketamine. The results showed that ketamine-treated male (KT-male) and female-in-diestrus (KTF-diestrus, the low estrogen phase) presented significant deficits in prepulse inhibition of the startle reflex and spatial working memory, two behavioral SCZ endophenotypes. On the contrary, female ketamine-treated rats during proestrus (KTF-proestrus, the high estradiol phase) had no behavioral alterations. This correlated with an oxidative imbalance in the hippocampus (HC) of both male and KTF-diestrus female rats, that is, decreased levels of GSH and increased levels of lipid peroxidation and nitrite. Similarly, BDNF was decreased in the KTF-diestrus rats while no alterations were observed in KTF-proestrus and male animals. The changes in the HC were in contrast to those in the prefrontal cortex in which only increased levels of nitrite in all groups studied were observed. Thus, there is a gender difference in the adult rat HC in response to ketamine neonatal administration, which is based on the estrous cycle. This is discussed in relation to neuropsychiatric conditions and in particular SCZ.