Biomedical subjects

Borja García-Bueno

Publications and source records attributed to Borja García-Bueno.

6 recordsLinked to original sources

PubMed2006

Effects of peroxisome proliferator-activated receptor gamma agonists on brain glucose and glutamate transporters after stress in rats.

Repeated stress causes an energy-compromised status in the brain, with a decrease in glucose utilization by the brain cells, which might account for excitotoxicity processes seen in this condition. In fact, brain glucose metabolism mechanisms are impaired in some neurodegenerative disorders, including stress-related neuropsychopathologies. More recently, it has been demonstrated that some synthetic peroxisome proliferator-activated receptor gamma (PPARgamma) agonists increase glucose utilization in rat cortical slices and astrocytes, as well as inhibit brain oxidative damage after repeated stress, which add support for considering these drugs as potential neuroprotective agents. To assess if stress causes glucose utilization impairment in the brain and to study the mechanisms by which this effect is achieved, young-adult male Wistar rats (control and immobilized for 6 h during 7 or 14 consecutive days, S7, S14) were i.p. injected with the natural ligand 15-deoxy-Delta-12,14-prostaglandin J2 (PGJ2, 120 microg/kg) or the high-affinity ligand rosiglitazone (RG, 3 mg/kg) at the onset of stress. Repeated immobilization during 1 or 2 weeks produces a decrease in brain cortical synaptosomal glucose uptake, and this effect was prevented by treatment with both natural and synthetic PPARgamma ligands by restoring protein expression of the neuronal glucose transporter, GLUT-3 in membrane fractions. On the other hand, treatment with PPARgamma ligands prevents stress-induced ATP loss in rat brain. Finally, repeated immobilization stress also produces a decrease in brain cortical synaptosomal glutamate uptake, and this effect was prevented by treatment with PPARgamma ligands by restoring synaptosomal protein expression of the glial glutamate transporter, EAAT2. In summary, our results demonstrate that 15d-PGJ2 and the thiazolidinedione rosiglitazone increase neuronal glucose metabolism, restore brain ATP levels and prevent the impairment in glutamate uptake mechanisms induced by exposure to stress, suggesting that this class of drugs may be therapeutically useful in conditions in which brain glucose levels or availability are limited after exposure to stress.

Adenosine Triphosphate↗

PubMed2006

Stress-induced oxidative changes in brain.

Numerous systems and organs are affected by stress. In this review we will focus on the effects in brain. Some of the most impressive effects of the stress in brain are the atrophy of hippocampal dendrites or even the reduction of the hippocampal size observed in brains from subjects exposed to severe or chronic stress. Obviously, before reaching this point of damage there are many other processes taking place in the stressed CNS. The release of glucocorticoids is one of the first features of the stress response. Glucocorticoids can result in neurotoxicity through different mechanisms, including modifications in the energy metabolism or via an increase in excitatory amino acids such as glutamate in the extracellular space. Glutamate can induce neuronal excitotoxicity. This sequence of events leads to the activation of TNFalpha convertase (TACE) and TNFalpha release in brain of rats subjected to restraint stress. One of the multiple effects exerted by this cytokine is to initiate the translocation of the transcription factor NFkappaB to neuronal nuclei. NFkappaB activation results in the induction of iNOS and COX2, two enzymes responsible for a great portion of the neurological damage produced in models of stress.

Animals↗

PubMed2005

Peroxisome proliferator-activated receptor gamma activation decreases neuroinflammation in brain after stress in rats.

BACKGROUND: A growing body of evidence has demonstrated that peroxisome proliferator-activated receptor gamma (PPARgamma) play a role in brain inflammatory conditions because various PPARgamma ligands inhibit proinflammatory mediators, such as cytokines (tumor necrosis factor alpha [TNFalpha]) and inducible nitric oxide synthase (NOS-2). As has been previously shown, immobilization stress and stress-related neuropsychologic conditions are followed by accumulation of oxidative/nitrosative mediators in brain after the release of cytokines, nuclear factor kappaB activation, and NOS-2 and cyclooxygenase 2 (COX-2) expression in the brain. METHODS: To assess whether PPARgamma activation can modify the accumulation of oxidative/nitrosative species seen in brain after stress, and to study the mechanisms by which this effect is achieved, young-adult male Wistar rats (control and immobilized during 6 hours) were injected (IP) with the high-affinity ligand rosiglitazone (RS) at the onset of stress. RESULTS: Stress increased PPARgamma expression in cortical neurons and glia as assessed by Western blot and immunohistochemistry. In stressed animals, RS (1-3 mg/kg) decreased stress-induced increases in NOS-2 activity. On the other hand, the PPARgamma ligand decreased stress-induced malondialdehyde (an indicator of lipid peroxidation) accumulation in cortex and prevented oxidation of the main antioxidant glutathione. The mechanisms involved in the antioxidative properties of RS in stress involve nuclear factor KB blockade (by preventing stress-induced IkappaBalpha decrease) and inhibition of TNFalpha release in stressed animals. At the doses tested, RS did not decrease COX-2 expression and prostaglandin E2 release during stress. Finally, RS also decreased chronic (repeated immobilization for 21 days) stress-induced accumulation of oxidative/nitrosative mediators. CONCLUSIONS: Taken together, these findings suggest a role for this antiinflammatory pathway in the brain response to stress and the possibility of pharmacologic modulation for preventing accumulation of oxidative/nitrosative species and subsequent brain damage in stress-related neuropsychologic conditions.

Animals↗

PubMed2005

The anti-inflammatory prostaglandin 15d-PGJ2 decreases oxidative/nitrosative mediators in brain after acute stress in rats.

RATIONALE: Immobilisation stress is followed by accumulation of oxidative/nitrosative mediators in brain after the release of tumour necrosis factor-alpha (TNFalpha) and other cytokines, nuclear factor kappa B (NFkappaB) activation, nitric oxide synthase-2 (NOS-2) and cyclooxygenase-2 (COX-2) expression in the brain. OBJECTIVES: This study was conducted to assess if some of the anti-inflammatory products of COX can modify the accumulation of oxidative/nitrosative species seen in brain after stress and to study the mechanisms by which this effect is achieved. METHODS: Young-adult male Wistar rats were subjected to a single session of immobilisation during 6 h. RESULTS: In stressed animals, brain levels of the anti-inflammatory 15d-PGJ2 increases concomitantly with COX-2 expression. Inhibition of COX-2 with NS-398 prevents stress-induced 15d-PGJ2 increase. Injection of supraphysiological doses of 15d-PGJ2 (80-120 microg/kg) decreases stress-induced increase in NOS-2 activity as well as the stress-induced increase in NO metabolites. On the other hand, 15d-PGJ2 decreases stress-induced malondialdehyde (an indicator of lipid peroxidation) accumulation in cortex and prevents oxidation of the main anti-oxidant glutathione. The mechanisms involved in the anti-oxidative properties of 15d-PGJ2 in stress involve NFkappaB blockade (by preventing stress-induced IkappaBalpha decrease) as well as inhibition of TNFalpha release in stressed animals. At the doses tested, 15d-PGJ2 decreases COX-2 expression and PGE2 release during stress, suggesting an alternative mechanism for this endogenous compound. CONCLUSIONS: These findings demonstrate a role for this anti-inflammatory pathway in the brain response to stress and open the possibility for preventing accumulation of oxidative/nitrosative species and subsequent brain damage.

Animals↗

PubMed2004

TNF-alpha accounts for short-term persistence of oxidative status in rat brain after two weeks of repeated stress.

Inducible nitric oxide synthase (NOS-2) accounts for the accumulation of oxidative and nitrosative mediators in brain after stress. To determine whether and when repeated exposure to immobilization stress leads to persistent oxidative status in rat brain, male Wistar rats were immobilized for 6 h/day for 7 or 14 days (S7, S14). Cerebral cortices were obtained immediately after the last session of stress or 1 day later. Stress increased NOS-2 activity after S7 or S14. This enzymatic activity returned to basal values 1 day after S7, but not 1 day after S14. Stress increased malondialdehyde (MDA) accumulation in cortex after S7 and S14. MDA levels returned to basal values 1 day after S7 but not 1 day after S14. In order to elucidate the possible mechanisms involved in this short-term persistence of oxidative status, brain levels of the cytokine tumour necrosis factor alpha (TNF-alpha) were determined. TNF-alpha levels did not increase after S7 or 1 day after S7, but increased after S14 and 1 day after S14. This was paralleled by an increase in TNF-alpha converting enzyme (TACE) activity in brain. When the increase in TNF-alpha at S14 was blocked by BB1101, an inhibitor of TACE, or its effects were blocked with anti-TNF-alpha, the accumulation of MDA and NOS-2 activity 1 day after S14 did not take place. These findings indicate that TACE and TNF-alpha account for stress-induced short-term persistence of NOS-2 activity and MDA accumulation after 14 days of repeated exposure and support a possible neuroprotective role for specific blockers of TNF-alpha in this situation.

Animals↗

PubMed2003

Relationship between cyclooxygenase-2 and nitric oxide synthase-2 in rat cortex after stress.

Many studies have focused on the relationships between distinct enzymatic sources of oxidative mediators. Recently, we have shown that cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (NOS-2) isoforms are up-regulated and account for oxidative damage in brain after stress. To assess the time course of these events, we have used adult male Wistar rats, some of which were immobilized for 6 h. Whereas pretreatment with the specific COX-2 inhibitor NS-398 (5 mg/kg i.p.) decreased Ca2+-independent NOS activity after 6 h of stress, pretreatment with the specific NOS-2 inhibitor 1400 W (4 mg/kg i.p.) did not decrease prostaglandin E2 (PGE2) accumulation induced by stress after 6 h. The observed effects of NS-398 and 1400 W were independent of the general response to stress--neither drug modified stress-induced corticosterone response--which might indicate a possible adaptive role for COX-2 and NOS-2 pathways in this situation. These findings are discussed as possible therapeutic targets in the context of neuropsychiatric disorders related to stress.

Amidines↗