Anna Maria Fernàndez Planas

A Concerted Appeal for International Cooperation in Preclinical Stroke Research

> Despite dramatic advances in the molecular pathogenesis of disease, translation of basic biomedical research into safe and effective clinical applications remains a slow, expensive, and failure-prone endeavor. > > Francis S. Collins1 The global burden of stroke on patients, their relatives, health systems, and the economies that support them is tremendous. In an unprecedented move, the World Health Organization (WHO) and the United Nations have responded to this challenge by declaring the fight against stroke a top priority in their drive to prevent and to control noncommunicable diseases.2 Indeed, great progress has been made in our understanding of stroke pathophysiology. This has led to the development of thrombolysis, a highly efficient therapy for a subset of patients with acute ischemic stroke. We came to realize that the responses of brain tissue to substrate deprivation are complex, and that not only neurons need to be considered but also glial and vascular cells, as well as local or blood-derived cells of the immune system.3–5 We now know that ischemia triggers a multitude of endogenous protective mechanisms in the brain which help to contain the ischemic lesion evolution and protect the brain from further damage.6 The brain has a tremendous capacity to overcome functional deficits, and as we begin to understand how brain plasticity works, we are actually finding evidence for tissue repair.7 We are also beginning to appreciate the interaction between the ischemic brain and the other organ systems, such as the immune system,8 the cardiovascular system, or systemic metabolism, a multidirectional signaling with tremendous impact on the outcome of patients with stroke.9 Taken together, research during the past few decades has suggested numerous targets for therapeutic intervention to restore perfusion, block mechanisms of damage, or induce endogenous mechanisms of protection, intercept deleterious signaling to …

Activation of ERK and Akt signaling in focal cerebral ischemia: Modulation by TGF-α and involvement of NMDA receptor

Cerebral ischemia activates ERK and Akt pathways. We studied whether these activations were affected by treatment with the protective growth factor transforming growth factor-alpha (TGF-alpha), and whether they were mediated through N-methyl D-aspartate (NMDA) receptors. The middle cerebral artery was occluded in rats and signaling was studied 1 h later. Noncompetitive NMDA receptor antagonist MK-801 was injected i.p. before the occlusion, whereas in other rats TGF-alpha was given intraventricularly before and after occlusion. Ischemia caused ERK phosphorylation in the nucleus, localized in the endothelium and neurons. Phosphorylation of ERK was prevented by TGF-alpha, but it was enhanced in the nucleus and cytoplasm by MK-801. Also, MK-801 but not TGF-alpha increased p-Akt. Results suggest that preventing ERK activation is related to the protective effect of TGF-alpha, whereas the protective effect of MK-801 is associated with activation of pro-survival Akt. While results support that NMDA receptor signaling precludes Akt activation, we did not find evidence to support that it underlies ischemia-induced ERK phosphorylation. This study illustrates that neuroprotection results from a fine balance between death and survival signaling pathways.

Brain tissue hypoxia and oxidative stress induced by obstructive apneas is different in young and aged rats.

STUDY OBJECTIVES To test the hypotheses that brain oxygen partial pressure (PtO2) in response to obstructive apneas changes with age and that it might lead to different levels of cerebral tissue oxidative stress. DESIGN Prospective controlled animal study. SETTING University laboratory. PARTICIPANTS Sixty-four male Wistar rats: 32 young (3 mo old) and 32 aged (18 mo). INTERVENTIONS Protocol 1: Twenty-four animals were subjected to obstructive apneas (50 apneas/h, lasting 15 sec each) or to sham procedure for 50 min. Protocol 2: Forty rats were subjected to obstructive apneas or sham procedure for 4 h. MEASUREMENTS AND RESULTS Protocol 1: Real-time PtO2 measurements were performed using a fast-response oxygen microelectrode. During successive apneas cerebral cortex PtO2 presented a different pattern in the two age groups; there was a fast increase in young rats, whereas it remained without significant changes between the beginning and the end of the protocol in the aged group. Protocol 2: Brain oxidative stress assessed by lipid peroxidation increased after apneas in young rats (1.34 ± 0.17 nmol/mg of protein) compared to old ones (0.63 ± 0.03 nmol/mg), where a higher expression of antioxidant enzymes was observed. CONCLUSIONS The results suggest that brain oxidative stress in aged rats is lower than in young rats in response to recurrent apneas, mimicking obstructive sleep apnea. This could be due to the different PtO2 response observed between age groups and the increased antioxidant expression in aged rats. CITATION Dalmases M, Torres M, Márquez-Kisinousky L, Almendros I, Planas AM, Embid C, Martínez-Garcia MA, Navajas D, Farré R, Montserrat JM. Brain tissue hypoxia and oxidative stress induced by obstructive apneas is different in young and aged rats.