Spinal cord injury by clip-compression induces anxiety and depression-like behaviours in female rats: The role of the inflammatory response.

Traumatic spinal cord injury (SCI) promotes long-term disability that affects mobility and functional independence. The spinal cord inflammatory response after the initial mechanical insult substantially impacts locomotor impairment and development of neuropsychiatric disorders, including anxiety and depression. However, these psychiatric events are scarcely investigated in females. This study investigated the anxiety/depression-like behaviours and inflammatory responses related to the production/release of pro- and anti-inflammatory cytokines in female adult Wistar rats submitted to severe clip-compression SCI. Data showed that SCI impaired the locomotor performance assessment by the BBB scale, but did not alter exploratory activity in open-field test. Animals' locomotor impairment was associated with anxious and depressive-like behaviours characterised by a decreased amount of time in the open arms of the elevated plus-maze test, and the motivational reduction of social interaction and anhedonia assessed by social exploration and sucrose preference tests. By contrast, SCI decreased the immobility time in the forced swimming test. Moreover, SCI caused a significant increase in local and systemic proinflammatory cytokines (TNF-α, INF-γ, IL-1ß, and IL-6) and a reduction in the anti-inflammatory cytokine IL-10. Finally, there were significant negative correlations between depression-like behaviour, but not anxiety, and increased plasma concentrations of TNF-α, IL-1ß, IL-6, and INF-γ. Additionally, the laminectomy procedure provoked the inflammatory response associated with reduced sucrose intake in Sham animals, although less expressively than in the SCI group. Collectively, these results indicate that SCI by clip-compression in female rats promotes a neuropsychiatric-like profile associated with an imbalance in the production/release of pro- and anti-inflammatory cytokines.

Implication of surgical procedure in the induction of headache and generalized painful sensation in a fluid percussion injury model in rats.

BACKGROUND: This study demonstrated the effects of traumatic brain injury (TBI) and each step of the surgical procedure for a fluid percussion injury (FPI) model on periorbital allodynia. NEW METHOD: Adult male Wistar rats were divided in naive, incision, scraping, sham-TBI and TBI groups. Periorbital allodynia was evaluated using von Frey filaments, and heat hyperalgesia of the hindpaws was evaluated by a Plantar Test Apparatus. RESULTS: The statistical analyses revealed that the surgical procedure decreased von Frey filaments thresholds twenty-four hours after the surgery in all groups when compared to the naive group (p < 0.0001). Scraping, sham-TBI and TBI groups showed a decrease in the periorbital mechanical threshold for 35 days compared with the naive and incision groups (p < 0.0001). Only the TBI group demonstrated a significant difference in periorbital allodynia at 45 and 60 days after the injury (p < 0.01). A significant decrease in the thermal withdrawal latency of the hindpaw contralateral to the lesion was observed in the TBI group compared with the naive group at 7 days and 28 days after the lesion (p < 0.05). COMPARISON WITH EXISTING METHODS: This study presented in detail the effects of each stage of the surgical procedure for a FPI model on periorbital allodynia over time and characterized the TBI model for this evaluation. CONCLUSION: The FPI model is relevant for the study of headache and generalized pain in both acute and chronic phases after an injury.

The Impact of Previous Physical Training on Redox Signaling after Traumatic Brain Injury in Rats: A Behavioral and Neurochemical Approach.

Throughout the world, traumatic brain injury (TBI) is one of the major causes of disability, which can include deficits in motor function and memory, as well as acquired epilepsy. Although some studies have shown the beneficial effects of physical exercise after TBI, the prophylactic effects are poorly understood. In the current study, we demonstrated that TBI induced by fluid percussion injury (FPI) in adult male Wistar rats caused early motor impairment (24 h), learning deficit (15 days), spontaneous epileptiform events (SEE), and hilar cell loss in the hippocampus (35 days) after TBI. The hippocampal alterations in the redox status, which were characterized by dichlorofluorescein diacetate oxidation and superoxide dismutase (SOD) activity inhibition, led to the impairment of protein function (Na(+), K(+)-adenosine triphosphatase [ATPase] activity inhibition) and glutamate uptake inhibition 24 h after neuronal injury. The molecular adaptations elicited by previous swim training protected against the glutamate uptake inhibition, oxidative stress, and inhibition of selected targets for free radicals (e.g., Na(+), K(+)-ATPase) 24 h after neuronal injury. Our data indicate that this protocol of exercise protected against FPI-induced motor impairment, learning deficits, and SEE. In addition, the enhancement of the hippocampal phosphorylated nuclear factor erythroid 2-related factor (P-Nrf2)/Nrf2, heat shock protein 70, and brain-derived neurotrophic factor immune content in the trained injured rats suggests that protein expression modulation associated with an antioxidant defense elicited by previous physical exercise can prevent toxicity induced by TBI, which is characterized by cell loss in the dentate gyrus hilus at 35 days after TBI. Therefore, this report suggests that previous physical exercise can decrease lesion progression in this model of brain damage.

Chronic administration of methylmalonate on young rats alters neuroinflammatory markers and spatial memory.

The methylmalonic acidemia is an inborn error of metabolism (IEM) characterized by methylmalonic acid (MMA) accumulation in body fluids and tissues, causing neurological dysfunction, mitochondrial failure and oxidative stress. Although neurological evidence demonstrate that infection and/or inflammation mediators facilitate metabolic crises in patients, the involvement of neuroinflammatory processes in the neuropathology of this organic acidemia is not yet established. In this experimental study, we used newborn Wistar rats to induce a model of chronic acidemia via subcutaneous injections of methylmalonate (MMA, from 5th to 28th day of life, twice a day, ranged from 0.72 to 1.67 µmol/g as a function of animal age). In the following days (29th-31st) animal behavior was assessed in the object exploration test and elevated plus maze. It was performed differential cell and the number of neutrophils counting and interleukin-1 beta (IL-1ß) and tumor necrosis factor-alpha (TNF-α) levels in the blood, as well as levels of IL-1ß, TNF-α, inducible nitric oxide synthase (iNOS) and 3-nitrotyrosine (3-NT) in the cerebral cortex were measured. Behavioral tests showed that animals injected chronically with MMA have a reduction in the recognition index (R.I.) when the objects were arranged in a new configuration space, but do not exhibit anxiety-like behaviors. The blood of MMA-treated animals showed a decrease in the number of polymorphonuclear and neutrophils, and an increase in mononuclear and other cell types, as well as an increase of IL-1ß and TNF-α levels. Concomitantly, MMA increased levels of IL-1ß, TNF-α, and expression of iNOS and 3-NT in the cerebral cortex of rats. The overall results indicate that chronic administration of MMA increased pro-inflammatory markers in the cerebral cortex, reduced immune system defenses in blood, and coincide with the behavioral changes found in young rats. This leads to speculate that, through mechanisms not yet elucidated, the neuroinflammatory processes during critical periods of development may contribute to the progression of cognitive impairment in patients with methylmalonic acidemia.

Exercise training prevents ecto-nucleotidases alterations in platelets of hypertensive rats.

In this study, we investigated the effect of 6 weeks of swimming training on the ecto-nucleotidase activities and platelet aggregation from rats that developed hypertension in response to oral administration of L-NAME. The rats were divided into four groups: control (n = 10), exercise (n = 10), L-NAME (n = 10), and exercise L-NAME (n = 10). The animals were trained five times per week in an adapted swimming system for 60 min with a gradual increase of the workload up to 5 % of animal's body weight. The results showed an increase in ATP, ADP, AMP, and adenosine hydrolysis, indicating an augment in NTPDase (from 35.3 ± 8.1 to 53.0 ± 15.1 nmol Pi/min/mg protein for ATP; and from 21.7 ± 7.0 to 46.4 ± 15.6 nmol Pi/min/mg protein for ADP as substrate), ecto-5'-nucleotidase (from 8.0 ± 5.7 to 28.1 ± 6.9 nmol Pi/min/mg protein), and ADA (from 0.8 ± 0.5 to 3.9 ± 0.8 U/L) activities in platelets from L-NAME-treated rats when compared to other groups (p < 0.05). A significant augment on platelet aggregation in L-NAME group was also observed. Exercise training was efficient in preventing these alterations in the exercise L-NAME group, besides showing a significant hypotensive effect. In conclusion, our results clearly indicated a protector action of moderate intensity exercise on nucleotides and nucleoside hydrolysis and on platelet aggregation, which highlights the exercise training effect to avoid hypertension complications related to ecto-nucleotidase activities.