Standardized extract of Erythrina velutina Willd. attenuates schizophrenia-Like behaviours and oxidative parameters in experimental animal models.

OBJECTIVES: To study the effects of the standardized extract from the leaves of Erythrina velutina in behavioural and oxidative parameters in the ketamine-induced schizophrenia model. METHODS: Mice received ketamine (KET) or saline for 7 days. From 8th to 14th day, the animals received Erythrine (Eryt) (100, 200 or 400 mg/kg) or olanzapine (Olanz), 1 h after KET administration. At 14th day, 30 min after the last administration of KET, the open-field and pre-pulse inhibition (PPI) tests were performed. Then, the animals were sacrificed and the prefrontal cortex (PFC), hippocampus (HC) and striatum (ST) were dissected for the oxidative tests. KEY FINDINGS: Ketamine increased spontaneous locomotor activity and grooming. KET decreased the PPI, which was reversed by combining it with Eryt or olanzapine. KET decreased GSH concentration in PFC and ST this was reversed by Eryt. KET increased MDA concentration in PFC and HC this was reversed by Eryt. Eryt and Olanzapine reduced MDA concentration in ST when compared to KET group. Nitrite concentration was reduced by administration of KET in the PFC. CONCLUSIONS: These results demonstrate that the standardized extract of E. velutina can prevent behavioural symptoms and oxidative stress induced by repeated doses of KET.

Ethanolic extract of Erythrina velutina Willd ameliorate schizophrenia-like behavior induced by ketamine in mice.

Background Schizophrenia is a chronic mental disorder, characterized by positive, negative and cognitive symptoms. In general, several plants have shown activity in diseases related to the central nervous system (e.g., Erythrina velutina (EEEV), also known as "mulungu"). For this reason, we aimed to investigate the effects of standardized ethanol extract obtained from the stem bark of EEEV on the schizophrenia-like behaviors induced by ketamine (KET) administration. Methods Swiss mice were treated with KET (20 mg/kg, i.p.) or saline for 14 days. In addition, from 8th to 14th days, saline, EEEV (200 or 400 mg/kg, p.o.) or olanzapine (OLAN 2 mg/kg, p.o.) were associated to the protocol. On the 14th day of treatment, schizophrenia-like symptoms were evaluated by the prepulse inhibition of the startle reflex (PPI), locomotor activity evaluated by the open field test (OFT), spatial recognition memory evaluated by the Y-maze task and social interaction test (SIT). Results KET has caused deficits in PPI, and it has also has caused hyperlocomotion in OFT and deficits in SIT as compared to control. EEEV in both doses used, reversed behavioral changes induced by KET, likewise results obtained with the administration of OLAN. Conclusions Taken together, the results demonstrate that the standard extract of EEEV was able to revert schizophrenia-like symptoms, due to the administration in repeated doses of ketamine. Thus, our findings lead to a new perspective for the use of EEEV an interesting alternative for drug discovery in schizophrenia.

Effects of standard ethanolic extract from Erythrina velutina in acute cerebral ischemia in mice.

The objective of this study was to verify a possible neuroprotective effect of the ethanolic extract of Erythrina velutina (EEEV). Male Swiss mice were submitted to transient cerebral ischemia by occlusion of both carotid arteries for 30 min and treated for 5 days with EEEV (200 or 400 mg/kg) or Memantine (MEM) 10 mg/kg, with initiation of treatment 2 or 24 h after Ischemia. On the 6th day after the induction of ischemia, the animals were submitted to evaluation of locomotor activity and memory and then sacrificed. The brains were dissected for the removal of the prefrontal cortex (PFC), hippocampus (HC) and striatum (ST) for determination of amino acid concentrations. In the step down and Y-maze tests, ischemia caused damage to the animals and treatment with EEEV or MEM reversed this effect. The animals submitted to ischemia also showed memory deficit in the object recognition test, an effect that was reverted by EEEV400 and MEM10. Amino acid dosage showed an increase in excitatory amino acid concentrations in the PFC of the ischemic animals and this effect was reversed by the treatment with EEEV400/24H. Regarding the inhibitory amino acids, ischemia caused an increase of taurine in the PFC while treatment with MEM10/24H or EEEV400/24H reversed this effect. In HC, an increase in excitatory amino acids was also observed in ischemiated animals having treatment with EEEV200/2H or EEEV400/24H reversed this effect. Similar effect was also observed in the same area in relation to the inhibitory amino acids with treatment with MEM10/24H or EEEV400/24H. In the ST, ischemia was also able to cause an increase in excitatory amino acids that was reversed more efficiently by the treatments with MEM10/24H and EEEV200. Also in this area, an increase of taurine and GABA was observed and only the treatment with EEEV200/2H showed a reversion of this effect. In view of these findings, EEEV presents a neuroprotective effect possibly due to its action on amino acid concentrations, and is therefore a potential therapeutic tool in reducing the damage caused by ischemia.

Antidepressant, antioxidant and neurotrophic properties of the standardized extract of Cocos nucifera husk fiber in mice.

The plant Cocos nucifera and its derivatives have shown antidepressant-like effects, although its hydroalcoholic extract has not been studied with this end in mind. Therefore, we decided to determine the antidepressant-like effects of the standardized hydroalcoholic extract of Cocos nucifera husk fiber (HECN) as well as oxidative alterations in the prefrontal cortex (PFC), hippocampus (HC) and striatum (ST), and the levels of brain-derived neurotrophic factor (BDNF) in the HC of mice. The extract was characterized based on the content of total polyphenols as well as two phenol compounds-catechin and chlorogenic acid-by HPLC-PDA. Male animals were treated per os (p.o.) for 7 days with distilled water or HECN (50, 100 or 200 mg/kg), or intraperitoneally with vitamin E (Vit E 400 mg/kg). One hour after the last drug administration, the animals were submitted to the open field test, forced swimming test (FST), tail suspension test (TST) and, immediately after the behavioral tests, had their brain removed for neurochemical determinations. The results showed that HECN100 decreased the immobility time in the FST and TST presenting, thus demonstrating an antidepressant-like effect. The administration of HECN decreased malondialdehyde levels in all doses and brain areas studied with the exception of HECN50 in the HC. The administration of HECN also decreased nitrite levels in all doses and brain regions studied. HECN100 also increased the levels of BDNF in HC of mice. In conclusion, we demonstrated that HECN has antidepressant-like properties, probably based on its antioxidant and neurotrophic effects, and is thus relevant for the treatment of depression.

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.

Effects of Kaurenoic Acid and Arginine on Random Skin Flap Oxidative Stress, Inflammation, and Cytokines in Rats.

BACKGROUND: Kaurenoic acid (KA), a diterpene extracted from copaíba oil-resin, is known to have potent antioxidant and anti-inflammatory properties. L-Arginine (LA) is an amino acid and a nitrogenous precursor for the synthesis of nitric oxide (NO). NO paper in wound healing has already been well documented. The aim of this study was to investigate the protective effects of LA and KA against ischemia reperfusion injury in a randomized skin flap model in rats. METHODS: A modified McFarlane flap model measuring 2.5 wide × 8 cm long was established in 36 anesthetized rats and evaluated within 3 groups: group control, group L-arginine, and group kaurenoic acid. Each group was subdivided into two subgroups (T1 and T2, n = 6 each). Samples were collected 24 h (T1)/48 h (T2) postoperatively for oxidative stress (glutathione), as non-protein thiols, malondialdehyde (MDA), NO2, inflammation [myeloperoxidase (MPO)], and cytokines TNF-α and IL-1ß assays. RESULTS: KA promoted a significant decrease of TNF-α and IL-1 expression and MPO activity at T1/T2 time points. NSGH levels increased significantly in KA-treated rats, while MDA levels decreased significantly in the same rats. Arginine promoted a significant decrease in MDA levels at the T1 time point and a significant increase in non-protein thiols concentrations at T1/T2 time points. NO2 concentration also decreased at the T1 time point. CONCLUSIONS: KA may attenuate the oxidative stress and the inflammation, thereby reducing tissue damage induced by ischemia/reperfusion in rats subjected to dorsal skin flaps. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors http://www.springer.com/00266.

Alpha-lipoic acid alone and combined with clozapine reverses schizophrenia-like symptoms induced by ketamine in mice: Participation of antioxidant, nitrergic and neurotrophic mechanisms.

Oxidative stress has important implications in schizophrenia. Alpha-lipoic acid (ALA) is a natural antioxidant synthesized in human tissues with clinical uses. We studied the effect of ALA or clozapine (CLZ) alone or in combination in the reversal of schizophrenia-like alterations induced by ketamine (KET). Adult male mice received saline or KET for 14 days. From 8th to 14th days mice were additionally administered saline, ALA (100 mg/kg), CLZ 2.5 or 5 mg/kg or the combinations ALA+CLZ2.5 or ALA+CLZ5. Schizophrenia-like symptoms were evaluated by prepulse inhibition of the startle (PPI) and locomotor activity (positive-like), social preference (negative-like) and Y maze (cognitive-like). Oxidative alterations (reduced glutathione - GSH and lipid peroxidation - LP) and nitrite in the prefrontal cortex (PFC), hippocampus (HC) and striatum (ST) and BDNF in the PFC were also determined. KET caused deficits in PPI, working memory, social interaction and hyperlocomotion. Decreased levels of GSH, nitrite (HC) and BDNF and increased LP were also observed in KET-treated mice. ALA and CLZ alone reversed KET-induced behavioral alterations. These drugs also reversed the decreases in GSH (HC) and BDNF and increase in LP (PFC, HC and ST). The combination ALA+CLZ2.5 reversed behavioral and some neurochemical parameters. However, ALA+CLZ5 caused motor impairment. Therefore, ALA presented an antipsychotic-like profile reversing KET-induced positive- and negative-like symptoms. The mechanism partially involves antioxidant, neurotrophic and nitrergic pathways. The combination of ALA+CLZ2.5 improved most of the parameters evaluated in this study without causing motor impairment demonstrating, thus, that possibly when combined with ALA a lower dose of CLZ is required.

Augmentation therapy with alpha-lipoic acid and desvenlafaxine: a future target for treatment of depression?

This study was designed to investigate the possible antidepressant effects of the antioxidant alpha-lipoic acid (ALA) as a stand-alone treatment or in association with desvenlafaxine (DVS) in the chronic corticosterone (CORT)-induced depression model. The depression model was induced by repeated administrations of CORT (20 mg/kg, subcutaneous) in mice over a period of 14 days. Between days 15 and 21, a randomized group of mice received DVS (10 or 20 mg/kg, per os [PO]), ALA (100 or 200 mg/kg, PO), or a combination of DVS (10 or 20 mg/kg, PO) and ALA (100 or 200 mg/kg, PO) along with the CORT injections for the remaining 7 days. Other groups of mice received DVS (10 or 20 mg/kg, PO) or ALA (100 or 200 mg/kg, PO) alone. Open field test, elevated plus maze (EPM) test, tail suspension test (TST), and forced swimming test (FST) were carried out 1 h after the last injection of CORT. Repeated CORT injections induced anxiety-like and depressive-like behaviors as observed by decreased open arms entries in the EPM test and increased immobility time in the TST and FST. The administration of DVS and ALA alone was able to reverse the increases in the immobility time. The combination of ALA and DVS potentiated the observed effects of DVS. These results suggest that augmentation therapy with the addition of antioxidant drugs may be an important pharmacological approach for the treatment of depression.