Assessment of antioxidant and antiparkinsonian potential of a new diterpene isolated from Croton argyrophylloides.

Oxidative stress is related to health problems including neurological and neurodegenerativedisturbs, such as Parkinson's disease. Natural compounds are reported as source of antioxidant molecules. Therefore, this study aimed to analyze the antioxidant and neuroprotective potential of a new diterpene isolated from C. argyrophylloides (MP-1). Male Wistar rats (250-300 g) were used to evaluate MP-1 antiparkinsonian potential through neurodegenerative model induced by the neurotoxin 6-hydroxydopamine (21 µg). On the 14th day, animals were submitted to behavioral tests and on the 15th day, brain areas were dissected to neurochemical analyzes. MP-1 demonstrated a high antioxidant capacity in vitro and decreased the parkinsonian effects, such as behavioral changes, motor alterations, and body weight loss. MP-1 was also able to control the upregulated levels of nitrosative stress and lipid peroxidation. These findings suggest MP-1 as a diterpene with high antioxidant capacity which might be used to development of new approach against Parkinson's disease.

Impact of eugenol on in vivo model of 6-hydroxydopamine-induced oxidative stress.

Oxidative stress is involved in many pathological disturbs, such as neurodegenerative disorders. Eugenol (Eug) is a phenolic compound with antioxidant and neuroprotective activities. Then, this study was conducted to investigate the potential neuroprotective effects of Eug on oxidative stress model induced by 6-hydroxydopamine (6-OHDA) in rats. First, the in vivo oxidative stress model was performed by intrastriatal injection (int.) of 6-OHDA (21 µg), followed by the treatment of Eug (0.1, 1, and 10 mg/kg/7 d) per os (p.o.). On the 7 d, behavioral tests were performed. On the 8 d, all the animals were euthanasied and their cerebral areas were excised for neurochemical and transcriptional analyses. The results showed that the treatment with Eug promoted neuroprotective effects on in vivo through reducing of oxidative stress and modulation of genes related to antioxidant activity. Furthermore, animals treated with Eug demonstrated returning of behavioral performance and body weight gain to normal conditions. Thus, this study reports the neuroprotective effects of Eug against oxidative stress induced by 6-OHDA in rats.

STRUCTURAL BASES OF GASTROINTESTINAL MOTILITY CHANGES IN PARKINSON'S DISEASE: STUDY IN RATS.

BACKGROUND: Gastrointestinal disorders are frequently reported in patients with Parkinson's disease whose disorders reduce the absorption of nutrients and drugs, worsening the clinical condition of patients. However, the mechanisms involved in modifying gastrointestinal pathophysiology have not yet been fully explained. AIM: To evaluate its effects on gastrointestinal motility and the involvement of the vagal and splanchnic pathways. METHODS: Male Wistar rats (250-300 g, n = 84) were used and divided into two groups. Group I (6-OHDA) received an intrastriatal injection of 6-hydroxydopamine (21 µg/animal). Group II (control) received a saline solution (NaCl, 0.9%) under the same conditions. The study of gastric emptying, intestinal transit, gastric compliance and operations (vagotomy and splanchnotomy) were performed 14 days after inducing neurodegeneration. Test meal (phenol red 5% glucose) was used to assess the rate of gastric emptying and intestinal transit. RESULTS: Parkinson's disease delayed gastric emptying and intestinal transit at all time periods studied; however, changes in gastric compliance were not observed. The delay in gastric emptying was reversed by pretreatment with vagotomy and splanchnotomy+celiac gangliectomy, thus suggesting the involvement of such pathways in the observed motor disorders. CONCLUSION: Parkinson's disease compromises gastric emptying, as well as intestinal transit, but does not alter gastric compliance. The delay in gastric emptying was reversed by truncal vagotomy, splanchnotomy and celiac ganglionectomy, suggesting the involvement of such pathways in delaying gastric emptying.

Structural bases of gastrointestinal motility changes in parkinson's disease: study in rats / Bases estruturais das alterações da motilidade gastrintestinal na doença de parkinson: estudo em ratos

ABSTRACT Background: Gastrointestinal disorders are frequently reported in patients with Parkinson's disease whose disorders reduce the absorption of nutrients and drugs, worsening the clinical condition of patients. However, the mechanisms involved in modifying gastrointestinal pathophysiology have not yet been fully explained. Aim: To evaluate its effects on gastrointestinal motility and the involvement of the vagal and splanchnic pathways. Methods: Male Wistar rats (250-300 g, n = 84) were used and divided into two groups. Group I (6-OHDA) received an intrastriatal injection of 6-hydroxydopamine (21 µg/animal). Group II (control) received a saline solution (NaCl, 0.9%) under the same conditions. The study of gastric emptying, intestinal transit, gastric compliance and operations (vagotomy and splanchnotomy) were performed 14 days after inducing neurodegeneration. Test meal (phenol red 5% glucose) was used to assess the rate of gastric emptying and intestinal transit. Results: Parkinson's disease delayed gastric emptying and intestinal transit at all time periods studied; however, changes in gastric compliance were not observed. The delay in gastric emptying was reversed by pretreatment with vagotomy and splanchnotomy+celiac gangliectomy, thus suggesting the involvement of such pathways in the observed motor disorders. Conclusion: Parkinson's disease compromises gastric emptying, as well as intestinal transit, but does not alter gastric compliance. The delay in gastric emptying was reversed by truncal vagotomy, splanchnotomy and celiac ganglionectomy, suggesting the involvement of such pathways in delaying gastric emptying.

RESUMO Racional: Distúrbios gastrintestinais são frequentemente relatados em pacientes com doença de Parkinson cujos distúrbios reduzem a absorção de nutrientes e fármacos, agravando o quadro clínico dos pacientes. No entanto, os mecanismos envolvidos na alteração da fisiopatologia gastrintestinal ainda não foram totalmente elucidados. Objetivo: Avaliar os seus efeitos sobre a motilidade gastrintestinal e o envolvimento das vias vagal e esplâncnica. Métodos: Ratos Wistar machos (250-300 g, n=84) foram utilizados e divididos em dois grupos. O grupo I (6-OHDA) recebeu injeção intraestriatal de 6-hidroxidopamina (21 µg/animal). O grupo II (controle) recebeu solução salina (NaCl, 0,9%) nas mesmas condições. O estudo do esvaziamento gástrico, trânsito intestinal, complacência gástrica e operações (vagotomia e esplancnotomia) foram realizadas 14 dias após a indução da neurodegeneração. Refeição teste (vermelho de fenol+glicose 5%) foi utilizada para avaliar a taxa de esvaziamento gástrico e o trânsito intestinal. Resultados: A doença de Parkinson retardou o esvaziamento gástrico e o trânsito intestinal em todos os tempos estudados; porém, alterações da complacência gástrica não foram observadas. O retardo do esvaziamento gástrico foi revertido por pré-tratamento com vagotomia e esplancnotomia+gangliectomia celíaca, sugerindo assim, o envolvimento de tais vias nos distúrbios motores observados. Conclusão: A doença de Parkinson compromete o esvaziamento gástrico, bem como o trânsito intestinal, mas não altera a complacência gástrica. O retardo do esvaziamento gástrico foi revertido pela vagotomia troncular, esplancnotomia e gangliectomia celíaca, sugerindo o envolvimento de tais vias no retardo do esvaziamento gástrico.

Neuroprotective Effects of Sulphated Agaran from Marine Alga Gracilaria cornea in Rat 6-Hydroxydopamine Parkinson's Disease Model: Behavioural, Neurochemical and Transcriptional Alterations.

Parkinson's disease (PD) is a multifactorial disease associated with the degeneration of dopaminergic neurons and behavioural alterations. Natural bioactive compounds may provide new therapeutic alternatives for neurodegenerative disorders, such as PD. The sulphated polysaccharides isolated from marine algae are heterogenic molecules that show different biological activities. The red marine alga Gracilaria cornea has a sulphated polysaccharide (SA-Gc) with structure and anti-inflammatory and antinociceptive activities reported in the literature. Therefore, this study aimed to evaluate the neuroprotective effects of SA-Gc in rat model PD induced by 6-hydroxydopamine (6-OHDA). Firstly, we established the PD model in rats, induced by an intrastriatal injection (int.) of 6-OHDA, followed by a single administration of SA-Gc (15, 30 or 60 µg; int.). On the 14th day, behavioural tests were performed. After killing, brain areas were dissected and used for neurochemical and/or transcriptional analyses. The results showed that SA-Gc (60 µg, int.) promoted neuroprotective effects in vivo through reducing the oxidative/nitroactive stress and through alterations in the monoamine contents induced by 6-OHDA. Furthermore, SA-Gc modulated the transcription of neuroprotective and inflammatory genes, as well as returning behavioural activities and weight gain to normal conditions. Thus, this study reports the neuroprotective effects of SA-Gc against 6-OHDA in rats.

Impact of the Chronic Omega-3 Fatty Acids Supplementation in Hemiparkinsonism Model Induced by 6-Hydroxydopamine in Rats.

Parkinson's disease (PD) is characterized by a progressive degeneration of dopaminergic neurons in the substantia nigra. The neuronal degeneration may result from the convergence of a number of different pathogenic factors, including apoptosis, excitotoxicity and oxidative stress. Many studies emphasize the importance of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) in vital processes such as maintenance of the properties of cell membranes and the participation in signal transduction and biodynamic activity of neuronal membranes. In this study, the protective effect of ω-3 PUFA administration on the 6-hydroxydopamine (6-OHDA) model of PD in rats was investigated. ω-3 PUFA (1.5 and 3.0 g/kg) was orally administered by gavage during 28 consecutive days to male Wistar rats. On the 4th day, hemiparkinsonism was induced through intrastriatal injection of 6-OHDA. On the 25th day, the animals were submitted to behavioural analysis. On the 28th day, after euthanasia, the brain areas were collected for neurochemical evaluation. ω-3 PUFAs (1.5 and 3.0 g/kg) restored monoamine and amino acid levels on the striatum from hemiparkinsonian rats, followed by reduction in the number of apomorphine-induced rotations and promotion of a partial locomotor recovery. In addition, ω-3 PUFAs (1.5 and 3.0 g/kg) decreased the lipid peroxidation levels and nitrite levels in the brain areas from hemiparkinsonian rats. Thus, this study suggests that supplementation with ω-3 PUFAs prevents behavioural and neurochemical disturbances induced by 6-OHDA, presenting a potential neuroprotective action.

Behavioral and neurochemical effects of alpha-lipoic Acid in the model of Parkinson's disease induced by unilateral stereotaxic injection of 6-ohda in rat.

This study aimed to investigate behavioral and neurochemical effects of α -lipoic acid (100 mg/kg or 200 mg/kg) alone or associated with L-DOPA using an animal model of Parkinson's disease induced by stereotaxic injection of 6-hydroxydopamine (6-OHDA) in rat striatum. Motor behavior was assessed by monitoring body rotations induced by apomorphine, open field test and cylinder test. Oxidative stress was accessed by determination of lipid peroxidation using the TBARS method, concentration of nitrite and evaluation of catalase activity. α -Lipoic acid decreased body rotations induced by apomorphine, as well as caused an improvement in motor performance by increasing locomotor activity in the open field test and use of contralateral paw (in the opposite side of the lesion produced by 6-OHDA) at cylinder test. α -lipoic acid showed antioxidant effects, decreasing lipid peroxidation and nitrite levels and interacting with antioxidant system by decreasing of endogenous catalase activity. Therefore, α -lipoic acid prevented the damage induced by 6-OHDA or by chronic use of L-DOPA in dopaminergic neurons, suggesting that α -lipoic could be a new therapeutic target for Parkinson's disease prevention and treatment.

Cocaine-induced status epilepticus and death generate oxidative stress in prefrontal cortex and striatum of mice.

Oxidative stress (OS) has been related to cocaine's actions and also to numerous nervous system pathologies, including seizures. The purpose of this work was to determine the alterations in glutathione (GSH) content, nitrite/nitrate and MDA levels after cocaine-induced toxicity. Male Swiss mice were injected (i.p.) with cocaine 90 mg/kg and observed during 1h. After this cocaine overdose some animals presented status epilepticus (SE) while some died after seizures. These animals were divided in two groups, SE and death. A group with an association of the antioxidant Vitamin E (Vit E, 400mg/kg, i.p.) plus Coc 90 (Vit E plus Coc 90) was undertaken to assess the neuroprotective effect of Vit E. Neurochemical analyses were carried out in prefrontal cortex (PFC) and striatum (ST). GSH levels increased only after cocaine-induced death in both areas studied. Cocaine-induced SE has increased nitrite/nitrate content in PFC and ST, while after death the increase was only in PFC. MDA (the lipid peroxidation marker) was elevated after SE and death in ST and only after death in PFC. Antioxidant treatment significantly reduced the GSH, nitrite/nitrate in ST and MDA levels. Only nitrite/nitrate content in PFC has not been decreased by Vit E pretreatment. The results relate that oxidative stress occurs after cocaine-induced toxicity mainly after death indicating that probably the increase of OS in the animal's brain leads to seizures and death, also showing a protective effect of Vit E in this process. Together with previous results this study contributes to the knowledge of cocaine-induced toxicity and possible in the near future to the use of antioxidants in the prevention of cocaine-induced CNS toxicity.

Antagonismo do receptor da adenosina A2a: nova perspectiva para o tratamento da doença de Parkinson [manuscrito] / Antagonism of A2A adenosine receptor: a new perspective for the treatment of Parkinson's disease [manuscript]

A doença de Parkinson (DP) é uma desordem neurodegenerativa, caracterizada pela destruição dos neurônios nigroestriatais dopamnérgicos. O tratamento atual para esta doença está restiro ao alívio sintomático, porque até o presente momento não existem agentes capazes de inibir a degeneração neuronal. Existem evidências experimentais de que antagonistas de receptores A2a da adenosina poderiam ser úteis no tratamento de DP. Com a cafeína e do CSC (8-(3-chlorostyryl caffeine)) no comportamento rotacional e nas alterações neuroquímicas em ratos lesionados com 6-OHDA, como modelo da doença de Parkinson. Os animais (ratos Wistar machos, 250-280g) foram tratados com cafeína (10 e 20mg/kg, i.p.) diariamente durante 14 dias, iniciando 1h após a lesão ou 7 dias, iniciando seis dias após a lesão com 6-OHDA ou com CSC (1 e 5mg/kg, i.p.) diariamente durante 7 dias, iniciando 6 dias após a lesão com 6-OHDA, sozinho ou associado com L-DOPA (CSC 1mg/kg, i.p. + L-DOPA 50mg/kg + Benzerazida 12,5mg/kg, i.p.). Os resultados mostraram que houve um aumento significativo do número de rotações induzidas por apomorfina nos animais lesionados com 6-OHDA (50 vezes) quando comparados aos animais falso operados...

Neuroprotective effects of caffeine in the model of 6-hydroxydopamine lesion in rats.

The work shows the effects of caffeine after the intrastriatal injection of 6-OHDA in rats, considered as a model of Parkinson disease (PD). Two weeks after the 6-OHDA lesion, rats exhibit a characteristic rotation behavior as a response to the apomorphine challenge. Our results showed significant increases in the number of apomorphine-induced rotations in 6-OHDA-lesioned rats, as compared to sham-operated animals. A partial recovery was observed in 6-OHDA-lesioned rats, after caffeine (10 and 20 mg/kg, i.p., daily for 14 days) treatment. The stereotaxic injection of 6-OHDA produced loss of striatal neurons, as indicated by the decrease in monoamines levels, in the ipsilateral side (75-85%) when compared to the contralateral side. Significant decreases in noradrenaline levels were seen in the ipsilateral side of 6-OHDA group (62%), and this effect was not significantly reversed in caffeine-treated groups. While significant decreases in dopamine levels were seen in the ipsilateral side of 6-OHDA group (78%), in the caffeine-treated group (10 and 20 mg/kg, i.p.) the decreases were only 53 and 18%, indicating significant recoveries. In conclusion, our data demonstrated beneficial effects of caffeine in this model of PD, suggesting the potential use of A2A antagonists as a novel treatment for this neurodegenerative disease.

Cocaine alters catalase activity in prefrontal cortex and striatum of mice.

Catalase is one of the enzymes that convert hydrogen peroxide (H2O2) to H2O presenting a protective role against free radicals. In this study, catalase activity was determined in homogenates of striatum (ST) and prefrontal cortex (PFC) in order to examine the participation of oxidative stress (OS) on cocaine actions in mice brain. Male Swiss mice were injected (i.p.) with cocaine at low (10 and 30 mg/kg) and high doses (90 mg/kg), and observed for 1 h. After cocaine overdose (90 mg/kg) some animals presented only status epilepticus (SE) while others died after seizures. These animals were dissected and divided in two groups, SE and death. Catalase activity was also determined after pretreatment with the anticonvulsant drug, diazepam, alone or injected before cocaine 90 mg/kg, and after seizures induced by a high dose of bupropion, a known inhibitor of NE and DA reuptake used for comparison. Results showed a decrease in catalase activity of the PFC and ST after SE and death induced by cocaine and bupropion overdoses. Cocaine at low doses decreased the enzyme activity only in ST. Diazepam treatment alone and before cocaine overdose did not interfere with catalase activity. This reduction in catalase activity may reflect an increase in H2O2 content in PFC and ST. Previous data reports that H2O2 inhibits dopamine transporter activity, suggesting that the decrease in catalase activity may potentiate the toxic mechanism of drugs that inhibit monoamines reuptake. As far as we know, this is the first report showing an involvement of OS in the cocaine's central mechanism of action.

Motivacao, vias neuronais e drogas de abuso / Motivation, neuronal pathways and drug abuse

Acredita-se que o estado motivacional de um organismo seja controlado, de modo importante, por processos reguladores homeostaticos basicos essenciais para a sobrevivencia. O hipotalamo, por suas funcoes integrativas, parece ser uma estrutura ideal do centro de controle da motivacao, assim como....