Patrícia Xavier Lima Gomes

Evidences for a progressive microglial activation and increase in iNOS expression in rats submitted to a neurodevelopmental model of schizophrenia: Reversal by clozapine

Schizophrenia was proposed as a progressive neurodevelopmental disorder. In this regard herein we attempted to determine progressive inflammatory and oxidative alterations induced by a neonatal immune challenge and its possible reversal by clozapine administration. For this end, Wistar rats at postnatal day (PN) 5-7 were administered the viral mimetic polyriboinosinic-polyribocytidilic acid (polyI:C) or saline. A distinct group of animals additionally received the antipsychotic drug clozapine (25mg/kg) from PN60 to 74. At PN35 (periadolescence), 60 (adult) and 74 (adulthood) the animals were submitted to behavioral determinations of prepulse inhibition of the startle (PPI) and Y maze task for working memory evaluation. At PN35 and 74 the animals were sacrificed and the hippocampus (HC), prefrontal cortex (PFC) and striatum (ST) immunostained for Iba-1, a microglial marker, and inducible nitric oxide synthase (iNOS). At PN74 oxidative stress parameters, such as, reduced glutathione levels (GSH) and lipid peroxidation were determined. The results showed a progressive increase of microglial activation and iNOS immunostaining from PN35 to PN74 mainly in the CA2 and CA3 regions of the HC and in the ST. At PN74 neonatal challenge also induced an oxidative imbalance. These inflammatory alterations were accompanied by deficits in PPI and working memory only in adult life that were reversed by clozapine. Clozapine administration reversed microglial activation and iNOS increase, but not the alterations of oxidative stress parameters. Taken together these results give further evidences for a neuroprogressive etiology and course of schizophrenia and that clozapine may partly alleviate this process.

Evidence for protective effect of lipoic acid and desvenlafaxine on oxidative stress in a model depression in mice.

Oxidative stress is implicated in the neurobiology of depression. Here we investigated oxidative alterations in brain areas of animals submitted to the model of depression induced by corticosterone (CORT) and the effects of the antioxidant compound alpha-lipoic acid (ALA) alone or associated with the antidepressant desvenlafaxine (DVS) in these alterations. Female mice received vehicle or CORT (20 mg/kg) during 14 days. From the 15th to 21st days different animals received further administrations of: vehicle, DVS (10 or 20 mg/kg), ALA (100 or 200 mg/kg), or the combinations of DVS10+ALA100, DVS20+ALA100, DVS10+ALA200, or DVS20+ALA200. Twenty-four hours after the last drug administration prefrontal cortex (PFC), hippocampus (HC) and striatum (ST) were dissected for the determination of the activity of superoxide dismutase (SOD), reduced glutathione (GSH) and lipid peroxidation (LP) levels. CORT significantly increased SOD activity in the PFC and HC, decreased GSH levels in the HC and increased LP in all brain areas studied when compared to saline-treated animals. Decrements of SOD activity were observed in all groups and brain areas studied when compared to controls and CORT. The hippocampal decrease in GSH was reversed by ALA100, DVS10+ALA100, DVS20+ALA100 and DVS20+ALA200. The same DVS+ALA combination groups presented increased levels of GSH in the PFC and ST. The greater GSH levels were observed in the PFC, HC and ST of DVS20+ALA200 mice. LP was reversed in the groups ALA200 (PFC), DVS10+ALA100, DVS20+ALA100 (PFC, HC and ST), and DVS20+ALA200 (PFC, HC). Our findings contribute to the previous preclinical evidences implicating ALA as a promising agent for augmentation therapy in depression.

Inhibition of ketamine‐induced hyperlocomotion in mice by the essential oil of Alpinia zerumbet: possible involvement of an antioxidant effect

Objectives  The antipsychotic, hypnotic, myorelaxant and antioxidant effects of the essential oil of Alpinia zerumbet (EOAZ) were studied.

B vitamins attenuate haloperidol-induced orofacial dyskinesia in rats: possible involvement of antioxidant mechanisms

Tardive dyskinesia (TD) is a serious motor disorder related to antipsychotic therapy, whose pathophysiology is associated to oxidative stress. Treatments that maintain antipsychotic efficacy while reducing TD risk are awaited. Haloperidol (HAL), a typical antipsychotic, is used as a putative murine model of TD. Here, we evaluated the protective role of vitamins B1, B6, and B12 alone or in combination (vitamin B cocktail) in preventing the HAL-induced orofacial dyskinesia (OD), based on their antioxidant properties. HAL (1 mg/kg) administered intraperitoneally to Wistar rats for 21 days caused OD and increased catalepsy time. The daily administration of B vitamins (B1 : B6 : B12 at 60 : 60 : 0.6 mg/kg) alone or the vitamin B cocktail, along with HAL, prevented the development of OD. Catalepsy time reduced in all groups treated with B vitamins, but to a lesser extent than OD. The participation of oxidative stress was assessed by the determination of reduced glutathione (GSH) levels and lipid peroxide formation in the striatum. HAL significantly decreased GSH levels and enhanced lipid peroxidation, whereas B1, B12, and vitamin B cocktail prevented the decrease in GSH levels. All groups treated with B vitamins presented a decrease in lipid peroxide formation. The data suggest a promising role for B vitamins in the prevention of OD.

N-acetylcysteine attenuates nicotine-induced kindling in female periadolescent rats

Kindling is a form of behavioral sensitization that is related to the progression of several neuropsychiatric disorders such as bipolar disorder. We recently demonstrated that female periadolescent rats are more vulnerable to nicotine (NIC)-induced kindling than their male counterparts. Furthermore, we evidenced that decreases in brain antioxidative defenses may contribute to this gender difference. Here we aimed to determine the preventive effects of the antioxidant N-acetyl cysteine (NAC) against NIC-kindling in female periadolescent rats. To do this female Wistar rats at postnatal day 30 received repeated injections of NIC 2mg/kg, i.p. every weekday for up to 19 days. NAC90, 180 or 270 mg/kg, i.p. was administered 30 min before NIC. The levels of glutathione (GSH), superoxide dismutase (SOD) activity, lipid peroxidation (LP) and nitrite were determined in the prefrontal cortex (PFC), hippocampus (HC) and striatum (ST). The development of kindling occurred at a median time of 16.5 days with 87.5% of NIC animals presenting stage 5 seizures in the last day of drug administration. NAC270 prevented the occurrence of kindling. NIC-kindled animals presented decreased levels of GSH and increased LP in the PFC, HC and ST, while SOD activity was decreased in the ST. NAC180 or 270 prevented the alterations in GSH induced by NIC, but only NAC270 prevented the alterations in LP. Nitrite levels increased in the ST of NAC270 pretreated NIC-kindled animals. Taken together we demonstrated that NAC presents anti-kindling effects in female animals partially through the restoration of oxidative alterations.