Antonio Moretti

Are reactive oxygen species involved in Alzheimer's disease?

Alzheimers disease has a multifactorial pathogenesis. Among the various factors involved, this review examines, in particular, the possibility of oxidative stress, meaning an imbalance between the formation and spread of reactive oxygen species (ROS) and the antioxidant defenses. This theory is supported by the following observations: (a) the alteration of mitochondrial function, which is likely to lead to the electron leakage in the respiratory chain and the consequent formation of superoxide radicals; (b) the unbalanced high activity of superoxide dismutase and monoamine oxidase B which causes the production of more H2O2; (c) the alteration of iron homeostasis which, in combination with the superoxide and H2O2, gives rise to the most deleterious hydroxyl radicals; (d) the increased lipid peroxidation and membrane alterations; (e) the pro-aggregating effect of ROS on beta/A4 protein and the C-terminal fragment of amyloid precursor (A4CT). Most of these changes are already present in the normal aging brain but are aggravated in AD presumably over a number of years. However, further investigations are needed to confirm these theories particularly regarding the alterations of another target of ROS, the proteins. Peroxidative stress is presumably present in the AD brain. This stress might not be a primary factor in the pathogenesis of AD, but a consequence of the tissue injury. In any case, it could contribute considerably to the pathology, in a vicious cycle of actions and reactions resulting in a critical mass of metabolic errors, responsible in the end for this disease.

Age- and peroxidative stress-related modifications of the cerebral enzymatic activities linked to mitochondria and the glutathione system

The aging brain undergoes a process of enhanced peroxidative stress, as shown by reports of altered membrane lipids, oxidized proteins, and damaged DNA. The aims of this review are to examine: (1) the possible contribution of mitochondrial processes to the formation and release of reactive oxygen species (ROS) in the aging brain; and (2) the age-related changes of antioxidant defenses, both enzymatic and nonenzymatic. It will focus on studies investigating the role of the electron transfer chain as the site of ROS formation in brain aging and the alterations of the glutathione system, also in relation to the effects of exogenous pro-oxidant agents. The possible role of peroxidative stress in age-related neurodegenerative diseases will also be discussed.

Affective disorders, antidepressant drugs and brain metabolism.

There is increasing evidence that affective disorders are associated with dysfunction of neurotransmitter postsynaptic transduction pathways and that chronic treatment with clinically active drugs results in adaptive modification of these pathways. Despite the close dependence of signal transduction on adenosine triphosphate (ATP) availability, the changes in energy metabolism in affective disorders are largely unknown. This question has been indirectly dealt with through functional imaging studies (PET, SPECT, MRS). Despite some inconsistencies, PET and SPECT studies suggest low activity in cortical (especially frontal) regions in depressed patients, both unipolar and bipolar, and normal or increased activity in the manic pole. Preliminary MRS studies indicate some alterations in brain metabolism, with reduced creatine phosphate and ATP levels in the brain of patients with affective disorders. However, the involvement of the energy metabolism in affective disorders is still debated. We propose direct neurochemical investigations on mitochondrial functional parameters of energy transduction, such as the activities of (a) the enzymatic systems of oxidative metabolic cycle (Krebs cycle); (b) the electron transfer chain; (c) oxidative phosphorylation, and (d) the enzyme activities of ATP-requiring ATPases. These processes should be studied in affective disorders and in animals treated with antidepressant drugs or lithium.

Pharmacological therapy of acute ischaemic stroke: Achievements and problems

Acute ischaemic stroke (AIS) is a leading cause of death and disability worldwide. Its incidence and prevalence increase considerably with age and numbers will grow with an ageing population. Consequently, the impact of AIS on costs is soaring. AIS is caused by the abrupt occlusion of an intracranial vessel resulting in reduced blood flow to the brain region supplied. The ischaemic core (which is irreversibly lesioned) is surrounded by the penumbra region with less severe flow reduction, lower functional impairment and potential recovery. Therefore, the fundamental treatment of AIS relies on prompt recanalisation and reperfusion of the threatened, but potentially salvageable, ischaemic penumbra. With this aim, intravenous thrombolysis with recombinant tissue plasminogen activator (rtPA) remains the current strategy. However, thrombolysis is underused, owing to various exclusion criteria that limit the number of treated patients. Other thrombolytics are under investigation. Endovascular therapy with mechanical recanalisation devices is also increasingly applied, though definite evidence of its benefit is lacking. Moreover, hypertension and hyperglycaemia are acute complications to be treated in AIS. This review analyses the current status, the problems, the perspectives and the cost-effectiveness of the pharmacological therapy for AIS.

Chapter 6 Contribution of Mitochondrial Alterations to Brain Aging

Publisher Summary This chapter describes the key role of mitochondria in energy transduction in the brain, with particular emphasis on mitochondrial oxidative phosphorylation and electron transfer. It focuses on how brain mitochondria contribute to age-related changes. The possible contribution of oxidative stress to brain aging is also examined. The brain occupies only 2% of the total body weight. However, the cerebral tissue consumes at least 20% of the total oxygen intake by the body at rest. Indeed the brain has an active oxidative metabolism because it derives almost all of its energy from aerobic metabolism. A series of molecular complexes, consisting of various equipotential subunits located in the mitochondrial inner membrane, provide both the transduction of oxidative energy in protonmotive force and the use of proton energy in ATP synthesis. The key mitochondrial enzyme cytochrome oxidase may be assumed as a metabolic marker for neuronal activity. Mitochondria play a key role in energy metabolism, as they carry out oxidative phosphorylation.

Effects of Neuroprotectants Before and After Stroke: Statins and Anti-hypertensives

Neuroprotection, as an anjunct or alternative therapy to thrombolysis, may be a rational strategy to improve penumbra survival. Nevertheless, so far none of the neuroprotectants found active in preclinical studies have been translated into clinical use.

Is the Mg2+-ATP-dependent proton pumping activity of the synaptic vesicles a factor involved in the cerebral hypoxia ?

AbstractThe changes in the Mg2+-dependent V-type ATPase activity and the Mg2+-ATP-dependent H+ pumping activity of the synaptic vesicles from the cerebral cortex of rats submitted to intermittent chronic (4 weeks) mild or severe hypoxia were evaluated. The adaptation to the chronic severe hypoxia increases both the ATPase and the H+ pumping activities which are inhibited by NEM with an exponential relationship between the IC50 values and the in vivo O2 concentration. The Mg2+-dependent increase in H+ pumping activity of synaptic vesicles from the rats subjected to in vivo chronic hypoxia may be antagonized by nigericin (dissipating ΔpH) and by FCCP (dissipating ΔpH and ΔΨSV). In contrast, valinomycin (dissipating the ΔΨSV and facilitating an enhancement in ΔpH) increases in vitro the H+ pumping activity that is inhibited by the addition of high concentration of K gluconate (reducing the rate of K+ efflux). The preincubation of vesicles from hypoxic rats with FCCP, but not with nigericin, inhibits the valinomycin-increased H+ pumping activity.l-glutamate increases the H+ pumping activity in synaptic vesicles from the cerebral cortex of chronic hypoxic rats, whereas other amino acids (i.e.,l-aspartate andl-homocysteate) and glutamate analogs (i.e., quisqualate and ibotenate) are ineffective. The adaptation to both chronic intermittent severe hypoxia and in vivo treatment with posatireline causes a decrease in the Mg2+-ATPase activity consistent with the decrease in the H+ pumping one of the synaptic vesicles. The addition of nigericin into incubation medium magnifies the decrease in the H+ pumping activity, while the addition of FCCP is ineffective, suggesting that the treatment with posatireline interferes with the ΔΨSV component in the

Neuroprotection for ischaemic stroke: Current status and challenges

\Delta \tilde \mu _{H^ + }