Neuroprotective effect of omega-3 polyunsaturated fatty acids in the 6-OHDA model of Parkinson's disease is mediated by a reduction of inducible nitric oxide synthase.

OBJECTIVE: Parkinson's disease (PD) is characterized by deterioration of the nigrostriatal system and associated with chronic neuroinflammation. Glial activation has been associated with regulating the survival of dopaminergic neurons and is thought to contribute to PD through the release of proinflammatory and neurotoxic factors, such as reactive nitric oxide (NO) that triggers or exacerbates neurodegeneration in PD. Polyunsaturated fatty acids (PUFAs) exert protective effects, including antiinflammatory, antiapoptotic, and antioxidant activity, and may be promising for delaying or preventing PD by attenuating neuroinflammation and preserving dopaminergic neurons. The present study investigated the effects of fish oil supplementation that was rich in PUFAs on dopaminergic neuron loss, the density of inducible nitric oxide synthase (iNOS)-immunoreactive cells, and microglia and astrocyte reactivity in the substantia nigra pars compacta (SNpc) and striatal dopaminergic fibers. METHODS: The animals were supplemented with fish oil for 50 days and subjected to unilateral intrastriatal 6-hydroxydopamine (6-OHDA)-induced lesions as a model of PD. RESULTS: Fish oil mitigated the loss of SNpc neurons and nerve terminals in the striatum that was caused by 6-OHDA. This protective effect was associated with reductions of the density of iNOS-immunoreactive cells and microglia and astrocyte reactivity. DISCUSSION: These results suggest that the antioxidant and antiinflammatory properties of fish oil supplementation are closely related to a decrease in dopaminergic damage that is caused by the 6-OHDA model of PD.

Fish oil improves anxiety-like, depressive-like and cognitive behaviors in olfactory bulbectomised rats.

Depression is increasingly present in the population, and its pathophysiology and treatment have been investigated with several animal models, including olfactory bulbectomy (Obx). Fish oil (FO) supplementation during the prenatal and postnatal periods decreases depression-like and anxiety-like behaviors. The present study evaluated the effect of FO supplementation on Obx-induced depressive-like behavior and cognitive impairment. Female rats received supplementation with FO during habituation, mating, gestation, and lactation, and their pups were subjected to Obx in adulthood; after the recovery period, the adult offspring were subjected to behavioral tests, and the hippocampal levels of brain-derived neurotrophic factor (BDNF), serotonin (5-HT) and the metabolite 5-hydroxyindoleacetic (5-HIAA) were determined. Obx led to increased anxiety-like and depressive-like behaviors, and impairment in the object location task. All behavioral changes were reversed by FO supplementation. Obx caused reductions in the levels of hippocampal BDNF and 5-HT, whereas FO supplementation restored these levels to normal values. In control rats, FO increased the hippocampal level of 5-HT and reduced that of 5-HIAA, indicating low 5-HT metabolism in this brain region. The present results indicate that FO supplementation during critical periods of brain development attenuated anxiety-like and depressive-like behaviors and cognitive dysfunction induced by Obx. These results may be explained by increased levels of hippocampal BDNF and 5-HT, two major regulators of neuronal survival and long-term plasticity in this brain structure.

The Antidepressant-Like Effect of Fish Oil: Possible Role of Ventral Hippocampal 5-HT1A Post-synaptic Receptor.

The pathophysiology of depression is not completely understood; nonetheless, numerous studies point to serotonergic dysfunction as a possible cause. Supplementation with fish oil rich docosahexaenoic (DHA) and eicosapentaenoic acids (EPA) during critical periods of development produces antidepressant effects by increasing serotonergic neurotransmission, particularly in the hippocampus. In a previous study, the involvement of 5-HT1A receptors was demonstrated and we hypothesized that fish oil supplementation (from conception to weaning) alters the function of post-synaptic hippocampal 5-HT1A receptors. To test this hypothesis, female rats were supplemented with fish oil during habituation, mating, gestation, and lactation. The adult male offspring was maintained without supplementation until 3 months of age, when they were subjected to the modified forced swimming test (MFST) after infusion of vehicle or the selective 5-HT1A antagonist, WAY100635, and frequency of swimming, immobility, and climbing was recorded for 5 min. After the behavioral test, the hippocampi were obtained for quantification of serotonin (5-HT) and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA) and for 5-HT1A receptor expression by Western blotting analysis. Fish oil-supplemented offspring displayed less depressive-like behaviors in the MFST reflected by decreased immobility and increased swimming and higher 5-HT hippocampal levels. Although there was no difference in the expression of hippocampal 5-HT1A receptors, intra-hippocampal infusion of a sub-effective dose of 8-OH-DPAT enhanced the antidepressant effect of fish oil in supplemented animals. In summary, the present findings suggest that the antidepressant-like effects of fish oil supplementation are likely related to increased hippocampal serotonergic neurotransmission and sensitization of hippocampal 5-HT1A receptors.

REM sleep deprivation reverses neurochemical and other depressive-like alterations induced by olfactory bulbectomy.

There is compelling evidence that sleep deprivation (SD) is an effective strategy in promoting antidepressant effects in humans, whereas few studies were performed in relevant animal models of depression. Acute administration of antidepressants in humans and rats generates a quite similar effect, i.e., suppression of rapid eye movement (REM) sleep. Then, we decided to investigate the neurochemical alterations generated by a protocol of rapid eye movement sleep deprivation (REMSD) in the notably known animal model of depression induced by the bilateral olfactory bulbectomy (OBX). REMSD triggered antidepressant mechanisms such as the increment of brain-derived neurotrophic factor (BDNF) levels, within the substantia nigra pars compacta (SNpc), which were strongly correlated to the swimming time (r = 0.83; P < 0.0001) and hippocampal serotonin (5-HT) content (r = 0.66; P = 0.004). Moreover, there was a strong correlation between swimming time and hippocampal 5-HT levels (r = 0.70; P = 0.003), strengthen the notion of an antidepressant effect associated to REMSD in the OBX rats. In addition, REMSD robustly attenuated the hippocampal 5-HT deficiency produced by the OBX procedure. Regarding the rebound (REB) period, we observed the occurrence of a sustained antidepressant effect, indicated mainly by the swimming and climbing times which could be explained by the maintenance of the increased nigral BDNF expression. Hence, hippocampal 5-HT levels remained enhanced in the OBX group after this period. We suggested that the neurochemical complexity inflicted by the OBX model, counteracted by REMSD, is directly correlated to the nigral BDNF expression and hippocampal 5-HT levels. The present findings provide new information regarding the antidepressant mechanisms triggered by REMSD.

Multiple intranigral unilateral LPS infusion protocol generates a persistent cognitive impairment without cumulative dopaminergic impairment.

Inflammation in Parkinson's disease (PD) is a continuous process and might be implicated in the progression of neuronal degeneration. Taking this into account, we proposed a new protocol with multiple and consecutive intranigral lipopolysaccharide (LPS) administration in order to analyze its effects on cognitive behavior. Additionally, striatal concentrations of the neurotransmitters dopamine (DA) and serotonin and their respective metabolites were assessed in three different time-points with the purpose of identifying the consecutive and cumulative effects of LPS infusions. We demonstrated that with a minimum administered dose there was stabilization of neuronal damage as revealed by absence of synergic effect on DA concentration. Although the DA decrease (-43%) generates an animal model of early phase of PD, without apparent motor impairment, the LPS group exhibited deficit in episodic-like memory behavior from the first time-point until the last one, indicating persisted disturbances in memory-recognition responses. These findings provide evidence that multiple intranigral LPS infusions are not sufficient to cause cumulative and progressive damage to dopaminergic neurons, but confirm that the LPS model can be adopted as a useful tool providing insight about the cognitive impairment observed in pre-motor phase of PD.

Efeitos da remobilização em duas semanas com natação sobre o músculo sóleo de ratos submetidos à imobilização / Effects of remobilization in two weeks of swimming on the soleus muscle of rats submitted to immobilization

Uma importante questão para a reabilitação é como proteger o músculo esquelético dos efeitos da imobilização, pois, o músculo é o mais mutável dentre os tecidos biológicos e responde às demandas normais ou alteradas com adaptações morfológicas e funcionais. O objetivo deste artigo foi verificar o efeito de duas diferentes intensidades de carga de natação sobre a morfologia do músculo sóleo, e se são eficazes para reverter o processo de atrofia causado pela imobilização durante o período de 15 dias. Foram utilizados 10 ratos, com idade de 10±2 semanas, divididos em 2 grupos: G1 (imobilização/natação sem peso) e G2 (imobilização/natação com sobrecarga de 10 por cento do peso corporal). Dentro das variáveis analisadas ao comparar o membro esquerdo (submetido à imobilização) com o direito (não submetido) foram observados: para peso muscular em G1=-20,55 por cento (p=0,0344) e G2= -17,02 por cento (p=0,0053); comprimento muscular em G1= -10,66 por cento (p=0,0011) e G2= -6,55 por cento (p=0,1016); estimativa de sarcômeros em série no músculo para G1= -14,18 por cento (p=0,0101) e G2= -10,99 por cento (p=0,0043); e para comprimento de sarcômeros em G1= 3,51 por cento (p=0,3989) e G2= 5,28 por cento (p=0,1771). Conclui-se que duas semanas de remobilização através da natação, com diferentes tipos de sobrecarga não foram suficientes para reverter totalmente o processo de atrofia causado pela imobilização.

An important issue in rehabilitation is how to protect the skeletal muscle from immobilization effects, since it is the most changeable tissue amongst the biological tissues and responds to normal or modified demands with morphological and functional adaptations. The objective of this paper was to check the effect of two different swimming load intensities on the morphological properties of the soleus muscle, and if the different degrees of swimming are effective to reverse the process of atrophy caused by immobilization during 15 days. Ten rats, 10±2 weeks were used and divided in 2 groups:G1(immobilization/swimming without overload) and G2 (immobilization/swimming with 10 percent overload). Within the variable analyzed, when the left limb (submitted to immobilization) was compared with the right limb (not submitted) it was observed: for muscle weight G1=-20.55 percent (p=0.0344) and G2= -17.02 percent (p=0.0053); for muscle length G1= -10.66 percent (p=0.0011) and G2= -6.55 percent (p=0.1016); for serial sarcomere estimate G1= -14.18 percent (p=0.0101) and G2= -10.99 percent (p=0.0043); and sarcomere length G1= 3.51 percent (p=0.3989) and G2= 5.28 percent (p=0.1771). It has been concluded that two weeks of remobilization through swimming, with different degrees of overload, were not sufficient to reverse the atrophy process caused by immobilization.