R F Villa

University of Pavia, Ticinum, Lombardy, Italy

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Publications (129)341.15 Total impact

  • Antonio Moretti, Federica Ferrari, Roberto F. Villa
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    ABSTRACT: Stroke is the third cause of death worldwide and the main cause of chronic, severe adult disability. We focus on acute ischaemic stroke, which accounts for approximately 80% of all strokes. The current therapy aims at restoring cerebral blood flow within a narrow time window in order to prevent damaging the “penumbra” which surrounds the infarct core. Intravenous thrombolysis remains the fundamental treatment worldwide, though not ideal for various restrictions and complications, limiting to 10% or less the percentage of patients treated within the appropriate time window. Neuroprotection is an alternative or adjunct approach to thrombolysis, targeting cerebral parenchyma in the acute ischaemic phase. Furthermore, neurorepair attempts to restore neuronal function in the after-stroke phase in those patients (treated or untreated) with significant impairment. In the past decades, the efficacy and safety of numerous candidate neuroprotective agents were showed in various animal stroke models. However, in clinical trials, promising pre-clinical studies have not been translated into positive outcomes. Our review will analyse the possible reasons for this failure and the new approaches and recommendations to overcome it, as well as novel strategies targeting additional events in ischaemia cascade. The combination of thrombolysis with pharmacological and non-pharmacological neuroprotective approaches has also been tested. Finally, the neurorepair strategy will be described with special emphasis on the role of cell-based therapies and ischaemic conditioning. Hopefully, the future therapy of ischaemic stroke will encompass a combination of neuroprotection (to stabilise penumbra), thrombolysis, antithrombotics (for secondary prevention) and neurorepair based on cell therapy plus rehabilitation.
    Pharmacology & Therapeutics. 01/2014;
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    ABSTRACT: The effect of aging on hippocampus is often confounded by diseases that commonly occur in the elderly. In this research, functional proteomics was used to characterize age-related changes in energy metabolism of different neuronal pathways within the hippocampus of Wistar rats aged 2, 6, 12, 18, and 24 months. The "large" synaptosomes, derived from glutamatergic mossy fiber endings connecting granule cells of dentate gyrus with apical dendrites of CA3 pyramidal cells, and the "small" synaptosomes, derived from the cholinergic small nerve endings of septo-hippocampal fibers, whose projections reach CA1 pyramidal cells, were isolated. Because most brain disorders are associated with bioenergetic changes, the maximum rate (Vmax) of selected enzymes of glycolysis, Krebs cycle, glutamate and amino acids metabolism, and acetylcholine catabolism were evaluated. The results show that "large" and "small" synaptosomes possess specific and independent metabolic features coherently with the selective vulnerability of the respective hippocampal subfields to Alzheimer's disease and cerebral ischemia. This study represents a reliable model to study in vivo (i) the physiopathological molecular mechanisms of some brain diseases dependent on energy metabolism, (ii) the responsiveness to noxious stimuli, and (iii) the effects of drugs, discriminating their action sites at subcellular level.
    Journal of Proteome Research 11/2013; · 5.06 Impact Factor
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    ABSTRACT: Stroke is a leading cause of death and disability, but most of the therapeutic approaches failed in clinical trials. The energy metabolism alterations, due to marked ATP decline, are strongly related to stroke and, at present, their physiopathological roles are not fully understood. Thus, the aim of this study was to evaluate the effects of aging on ischemia-induced changes in energy mitochondrial transduction and the consequences on overall brain energy metabolism in an in vivo experimental model of complete cerebral ischemia of 15 min duration and during post-ischemic recirculation after 1, 24, 48, 72 and 96 hrs, in 1 year "adult" and 2 year-old "aged" rats. The maximum rate (Vmax) of citrate synthase, malate dehydrogenase, succinate dehydrogenase for Krebs' cycle; NADH-cytochrome c reductase and cytochrome oxidase for electron transfer chain (ETC) were assayed in non-synaptic "free" mitochondria and in two populations of intra-synaptic mitochondria, i.e. "light" and "heavy" mitochondria. The catalytic activities of enzymes markedly differ according to: (a) mitochondrial type (non-synaptic, intra-synaptic), (b) age, (c) acute effects of ischemia and (d) post-ischemic recirculation at different times. Enzyme activities changes are injury maturation events and strictly reflect the bioenergetic state of the tissue in each specific experimental condition respect to the energy demand, as shown by the comparative evaluation of the energy-linked metabolites and substrates content. Remarkably, recovery of mitochondrial function was more difficult for intra-synaptic mitochondria in "aged" rats, but enzyme activities of energy metabolism tended to normalize in all mitochondrial populations after 96 hrs of recirculation. This observation is relevant for Therapy, indicating that mitochondrial enzymes may be important metabolic factors for the responsiveness of ischemic penumbra towards the restore of cerebral functions.
    Neurochemistry International 10/2013; · 2.66 Impact Factor
  • Roberto Federico Villa, Federica Ferrari, Antonella Gorini
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    ABSTRACT: The maximum rate (Vmax) of some enzymatic activities related to energy consumption was evaluated in synaptic plasma membranes from rat brain striatum, being the synaptic energy state a crucial factor in neurodegenerative diseases etiopathogenesis. Two types of synaptic plasma membranes were isolated from rats subjected to in vivo treatment with L-acetylcarnitine at two different doses (30 and 60 mg x kg(-1) i.p., 28 days, 5 days/week). The following enzyme activities were evaluated: Acetylcholinesterase (AChE); Na(+), K(+), Mg(2+)-ATP-ase; ouabain insensitive Mg(2+)-ATP-ase; Na(+), K(+)-ATP-ase; direct Mg(2+)-ATP-ase; Ca(2+), Mg(2+)-ATP-ase; low- and high-affinity Ca(2+)-ATP-ase. In control (vehicle-treated) animals, enzymatic activities are differently expressed in synaptic plasma membranes type I (SPM1) respect to synaptic plasma membranes type II (SPM2), being the evaluated enzymatic activities higher in SPM2. Subchronic treatment with L-acetylcarnitine decreased AChE on SPM1 and SPM2 at the dose of 30 mg x kg(-1). Pharmacological treatment decreased ouabain insensitive Mg(2+)-ATP-ase activity and high affinity Ca(2+)-ATP-ase activity at the dose of 30 and 60 mg x kg(-1) respectively on SPM1, while decreased Na(+), K(+)-ATP-ase, direct Mg(2+)-ATP-ase and Ca(2+), Mg(2+)-ATP-ase activities at the dose of 30 mg x kg(-1) on SPM2. These results suggest that the sensitivity to drug treatment is different between these two populations of synaptic plasma membranes from striatum, confirming the micro-heterogeneity of these subfractions, possessing different metabolic machinery respect to energy consumption and utilization and the regional selective affect of L-acetylcarnitine on cerebral tissue, depending on the considered area. The drug potential effect at the synaptic level in Parkinson's Disease neuroprotection is also discussed respect to acetylcholine and energy metabolism.
    Neuroscience 06/2013; · 3.12 Impact Factor
  • Roberto Federico Villa, Federica Ferrari, Antonella Gorini
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    ABSTRACT: The effect of aging and CDP-choline treatment (20 mg · kg(-1) body weight i.p. for 28 days) on the maximal rates (V(max)) of representative mitochondrial enzyme activities related to Krebs' cycle (citrate synthase, α-ketoglutarate dehydrogenase, malate dehydrogenase), glutamate and related amino acid metabolism (glutamate dehydrogenase, glutamate-oxaloacetate- and glutamate-pyruvate transaminases) were evaluated in non-synaptic and intra-synaptic "light" and "heavy" mitochondria from frontal cerebral cortex of male Wistar rats aged 4, 12, 18 and 24 months. During aging, enzyme activities vary in a complex way respect to the type of mitochondria, i.e. non-synaptic and intra-synaptic. This micro-heterogeneity is an important factor, because energy-related mitochondrial enzyme catalytic properties cause metabolic modifications of physiopathological significance in cerebral tissue in vivo, also discriminating pre- and post-synaptic sites of action for drugs and affecting tissue responsiveness to noxious stimuli. Results show that CDP-choline in vivo treatment enhances cerebral energy metabolism selectively at 18 months, specifically modifying enzyme catalytic activities in non-synaptic and intra-synaptic "light" mitochondrial sub-populations. This confirms that the observed changes in enzyme catalytic activities during aging reflect the bioenergetic state at each single age and the corresponding energy requirements, further proving that in vivo drug treatment is able to interfere with the neuronal energy metabolism.
    Neurochemistry International 10/2012; · 2.66 Impact Factor
  • R F Villa, F Ferrari, A Gorini
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    ABSTRACT: Ageing is one of the main risk factors for brain disorders. According to the neuroendocrine theory, ageing modifies the sensitivity of hypothalamus-pituitary-adrenal axis to homoeostatic signals coming from the cerebral cortex. The relationships between the energy metabolism of these areas have not been considered yet, in particular with respect to ageing. For these reasons, this study was undertaken to systematically investigate in female Sprague-Dawley rats aged 4, 6, 12, 18, 24, 28months and in 4-month-old male ones, the catalytic properties of energy-linked enzymes of the Krebs' cycle, electron transport chain, glutamate and related amino acids on different mitochondrial subpopulations, i.e. non-synaptic perikaryal and intra-synaptic (two types) mitochondria. The biochemical enzymatic pattern of these mitochondria shows different expression of the above-mentioned enzymatic activities in the investigated brain areas, including frontal cerebral cortex, hippocampus, striatum, hypothalamus and hypophysis. The study shows that: (i) the energy metabolism of the frontal cerebral cortex is poorly affected by physiological ageing; (ii) the biochemical machinery of non-synaptic perikaryal mitochondria is differently expressed in the considered brain areas; (iii) at 4-6months, hypothalamus and hypophysis possess lower oxidative metabolism with respect to the frontal cerebral cortex while (iv), during ageing, the opposite situation occurs. We hypothesised that these metabolic modifications likely try to grant HPA functionality in response to the incoming external stress stimuli increased during ageing. It is particularly notable that age-related changes in brain bioenergetics and in mitochondrial functionality may be considered as remarkable factors during physiological ageing and should play important roles in predisposing the brain to physiopathological events, tightly related to molecular mechanisms evoked for pharmacological treatments.
    Neuroscience 09/2012; 227C:55-66. · 3.12 Impact Factor
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    Roberto F. Villa, Federica Ferrari, Antonella Gorini
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    ABSTRACT: The maximum rates of adenosine triphosphatase (ATPase) systems related to energy consumption were systematically evaluated in synaptic plasma membranes isolated from the striata of male Wistar rats aged 2, 6, 12, 18, and 24 months, because of their key role in presynaptic nerve ending homeostasis. The following enzyme activities were evaluated: sodium-potassium-magnesium adenosine triphosphatase (Na+, K+, Mg2+-ATPase); ouabain-insensitive magnesium adenosine triphosphatase (Mg2+-ATPase); sodium-potassium adenosine triphosphatase (Na+, K+-ATPase); direct magnesium adenosine triphosphatase (Mg2+-ATPase); calcium-magnesium adenosine triphosphatase (Ca K+-ATPase decreased at 18 and 24 months, Ca2+, Mg2+-ATPase and acetylcholinesterase decreased from 6 months, while Mg2+-ATPase was unmodified. Therefore, ATPases vary independently during aging, suggesting that the ATPase enzyme systems are of neuropathological and pharmacological importance. This could be considered as an experimental model to study regeneration processes, because of the age-dependent modifications of specific synaptic plasma membranes. ATPases cause selective changes in some cerebral functions, especially bioenergetic systems. This could be of physiopathological significance, particularly in many central nervous system diseases, where, during regenerative processes, energy availability is essential.
    Neural Regeneration Research 01/2012; 7(1):6-12. · 0.14 Impact Factor
  • Roberto Federico Villa, Federica Ferrari, Antonella Gorini
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    ABSTRACT: The maximum rates (V (max)) of some enzymatic activities related to energy consumption (ATP-ases) were evaluated in two types of synaptic plasma membranes (SPM) isolated from cerebral cortex of rats subjected to in vivo treatment with L: -acetylcarnitine at two different doses (30 and 60 mg kg(-1) i.p., 28 days, 5 days/week). The following enzyme activities were evaluated: acetylcholinesterase (AChE); Na(+), K(+), Mg(2+)-ATP-ase; ouabain insensitive Mg(2+)-ATP-ase; Na(+), K(+)-ATP-ase; direct Mg(2+)-ATP-ase; Ca(2+), Mg(2+)-ATP-ase; Low- and High-affinity Ca(2+)-ATP-ase. Sub-chronic treatment with L: -acetylcarnitine increased Na(+), K(+)-ATP-ase activity on SPM 2 and Ca(2+), Mg(2+)-ATP-ase activity on both SPM fractions. These results suggest (1) that the sensitivity to drug treatment is different between the two populations of SPM, confirming the micro-heterogeneity of these sub-fractions, probably originating from different types of synapses, (2) the specificity of the molecular site of action of the drug on SPM and (3) its interference on ion homeostasis at synaptic level.
    Neurochemical Research 04/2011; 36(8):1372-82. · 2.13 Impact Factor
  • A Moretti, A Gorini, R F Villa
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    ABSTRACT: Vascular dementia (VAD), the second most common form of dementia after Alzheimer's disease (AD) is characterized by a cognitive deficit of cerebrovascular origin. As for AD, the main proposed treatment is based on cholinesterase inhibitors. However, randomized clinical trials (RCTs) with cholinesterase inhibitors in VAD reported modest - though sometimes statistically significant - clinical efficacy. Non-cholinergic drugs with diverse rationales and mechanisms of action have also been tested in a few RCTs for VAD; the outcomes measured are variable and the evidence of efficacy is weak. The limitations of pharmacological treatment for VAD have prompted a different strategy, i.e. primary prevention aimed at reducing vascular risk factors. Several epidemiological studies reported associations of hypertension, type 2 diabetes, obesity, and inflammation with VAD and in some cases, AD. These all coincide with those of stroke, which in turn is an established factor for cognitive decline and VAD. Here too, only a few RCTs have looked at prevention of these factors, except hypertension. Some pharmacological classes are particularly promising from the clinical and experimental viewpoints: Ca2+ channel blockers and drugs affecting the renin-angiotensin system may act independently of the effects on blood pressure. Despite some conflicting results and the need for further work, the control of risk factors might prevent cognitive decline and VAD in the elderly. The benefit of tackling vascular factors is probably larger when also considering the prevention of stroke. The objective of this review is to analyze the pharmacological treatment and prevention of VAD and their outcome. The literature on Pubmed from 1980 to 2009 was examined.
    CNS & neurological disorders drug targets 02/2011; 10(3):370-90. · 3.57 Impact Factor
  • Roberto Federico Villa, Federica Ferrari, Antonella Gorini
    Society for Neuroscience; 01/2011
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    ABSTRACT: The knowledge of coenzyme Q levels in tissues, organs, and subcellular compartments is of outstanding interest. A wide amount of data regarding coenzyme Q distribution and occurrence was collected in the last decades; nevertheless the data are often hard to compare because of the different extraction methods and different analytical techniques used. We have undertaken a systematic study for detecting the ubiquinone content in subcellular compartments, cells, and whole-tissue homogenates by a previously standardized HPLC method performed after an extraction procedure identical for all samples. It was confirmed that the major coenzyme Q homologue in rat tissues is coenzyme Q9; however, it was pointed out that all the rodents samples tested contain more than one coenzyme Q homologue. The coenzyme Q homologue distribution is tissue dependent with relatively high coenzyme Q10 content in brain mitochondria, irrespective of the rat strain used. There is no constant relationship of the coenzyme Q content in mitochondria and microsomes fractions. Most organisms tested (including other mammals, bird and fish specimens) have only coenzyme Q10, while the protozoan Tetrahymena pyriformis contains only coenzyme Q8.
    Membrane biochemistry 07/2009; 9(3):179-90.
  • Roberto Federico Villa, Antonella Gorini, Siegfried Hoyer
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    ABSTRACT: The effect of ageing and the relationships between the catalytic properties of enzymes linked to Krebs' cycle, electron transfer chain, glutamate and aminoacid metabolism of cerebral cortex, a functional area very sensitive to both age and ischemia, were studied on mitochondria of adult and aged rats, after complete ischemia of 15 minutes duration. The maximum rate (Vmax) of the following enzyme activities: citrate synthase, malate dehydrogenase, succinate dehydrogenase for Krebs' cycle; NADH-cytochrome c reductase as total (integrated activity of Complex I-III), rotenone sensitive (Complex I) and cytochrome oxidase (Complex IV) for electron transfer chain; glutamate dehydrogenase, glutamate-oxaloacetate-and glutamate-pyruvate transaminases for glutamate metabolism were assayed in non-synaptic, perikaryal mitochondria and in two populations of intra-synaptic mitochondria, i.e., the light and heavy mitochondrial fraction. The results indicate that in normal, steady-state cerebral cortex, the value of the same enzyme activity markedly differs according (a) to the different populations of mitochondria, i.e., non-synaptic or intra-synaptic light and heavy, (b) and respect to ageing. After 15 min of complete ischemia, the enzyme activities of mitochondria located near the nucleus (perikaryal mitochondria) and in synaptic structures (intra-synaptic mitochondria) of the cerebral tissue were substantially modified by ischemia. Non-synaptic mitochondria seem to be more affected by ischemia in adult and particularly in aged animals than the intra-synaptic light and heavy mitochondria. The observed modifications in enzyme activities reflect the metabolic state of the tissue at each specific experimental condition, as shown by comparative evaluation with respect to the content of energy-linked metabolites and substrates. The derangements in enzyme activities due to ischemia is greater in aged than in adult animals and especially the non-synaptic and the intra-synaptic light mitochondria seems to be more affected in aged animals. These data allow the hypothesis that the observed modifications of catalytic activities in non-synaptic and intra-synaptic mitochondrial enzyme systems linked to energy metabolism, amino acids and glutamate metabolism are primary responsible for the physiopathological responses of cerebral tissue to complete cerebral ischemia for 15 min duration during ageing.
    Neurochemical Research 07/2009; 34(12):2102-16. · 2.13 Impact Factor
  • R F Villa, A Gorini, S Hoyer
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    ABSTRACT: The effect of ageing on the activity of enzymes linked to Krebs' cycle, electron transfer chain and glutamate metabolism was studied in three different types of mitochondria of cerebral cortex of 1-year old and 2-year old male Wistar rats. We assessed the maximum rate (V(max)) of the mitochondrial enzyme activities in non-synaptic perikaryal mitochondria, and in two populations of intra-synaptic mitochondria. The results indicated that: (i) in normal, steady-state cerebral cortex the values of the catalytic activities of the enzymes markedly differed in the various populations of mitochondria; (ii) in intra-synaptic mitochondria, ageing affected the catalytic properties of the enzymes linked to Krebs' cycle, electron transfer chain and glutamate metabolism; (iii) these changes were more evident in intra-synaptic "heavy" than "light" mitochondria. These results indicate a different age-related vulnerability of subpopulations of mitochondria in vivo located into synapses than non-synaptic ones.
    Journal of Neural Transmission 12/2006; 113(11):1659-70. · 3.05 Impact Factor
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    A Moretti, A Gorini, R F Villa
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    ABSTRACT: 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 (Kreb's 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.
    Molecular Psychiatry 10/2003; 8(9):773-85. · 15.15 Impact Factor
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    ABSTRACT: Neurodegenerative Diseases represent the most common cause of Dementia, about 5-10% of the population aged above 65 years and about 30% above 80 years. A study about Apo-E alleles, Coenzyme Q and Vitamins E as biological indicators was performed in plasma samples of patients aged from 30 to 85 years, affected by Neurodegenerative Diseases. The results were compared with control subjects of approximately the same ages as the reference group. A frequency of 21.7% of epsilon4 allele in control group was estimated, against 15.8% observed in patients. The frequency of epsilon2 and epsilon3 alleles was 13.0% and 65.2% in the control group against 10.5% and 73.7% in patients. No significant differences were observed between the frequency of epsilon3/epsilon3 genotype and epsilon3/epsilon4 genotype in the control group compared to patients' group. The frequencies observed in epsilon2/epsilon3 genotype groups were 8.7% vs 15.8% and of e2/e4 genotype 17.4% vs 5.3%. The epsilon2/epsilon2 and epsilon4/epsilon4 genotypes were not identified in any groups. Plasma CoQ10 concentrations were similar in patient and control groups and no differences were found even taking into account the distribution of male and female subjects in the two groups. Also, vitamin E did not provide evidence of any differences between groups and the analysis among sexes revealed that again vitamin E concentrations were similar in between subgroups.
    BioFactors 02/2003; 18(1-4):277-81. · 3.09 Impact Factor
  • R F Villa, A Gorini, S Hoyer
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    ABSTRACT: Plasticity and relationships between individual ATPases linked to energy-utilizing systems of hippocampus, a very sensitive functional area to both age and ischemia, were studied during ageing on synaptic plasma membranes of 1-year-old "adult" and 2-year-old "aged" rats after 15 min of complete cerebral ischemia and different reperfusion times (01, 24, 48, 72, and 96 h). Activities of Na+, K+, Mg(2+)-ATPase, Mg(2+)-ATPase ouabain insensitive, Na+, K(+)-ATPase, "direct" or "basal" Mg(2+)-ATPase, and acetylcholinesterase (AChE) were evaluated in synaptic plasma membranes, where they play the major role in the regulation of presynaptic nerve ending homeostasis. This in vivo study of recovery time-course from 15 mins of cerebral ischemia indicated specific biochemical assessments of functional meaning: (a) Na+K(+)-ATPase of synaptic plasma membranes in adult and aged animals is stimulated by ischemia; (b) this "hyperactivity" is more markedly related to adult than to aged animals; (c) these abnormalities still persist after 72 and 96 h during the recirculation times, indicating the delayed postischemic suffering of the brain; (d) specific Mg(2+)-ATPase enzyme system possess a lower catalytic power in aged animals than in adult ones, but remained unaltered in adult animals by ischemia and reperfusion; (e) Mg(2+)-ATPase is stimulated in aged animals by ischemia, further increasing during reperfusion up to 72-96 h, indicating the delayed hyperactivity of hippocampus; (f) the increased metabolic activity of hippocampus is indicated by the increased activity of cholinergic system; (g) integrity of synaptic plasma membranes seems not to be altered by 15 min ischemia to a critical extent to compromise their catalytic functionality during reperfusion; (h) AChE activity increases in both adult and aged at some survival times. There are logical reasons for the hypothesis that the modifications in ATPase's catalytic activities in synaptic plasma membranes, which have been modified by ischemia in presynaptic terminals, may play important functional role during recovery time in cerebral tissue in vivo, especially as regards its responsiveness to noxious stimuli, particularly during the recirculation period from acute (or chronic) brain injury.
    Neurochemical Research 10/2002; 27(9):861-70. · 2.13 Impact Factor
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    ABSTRACT: Coenzyme Q distribution, as well as respiratory chain features, in rat brain mitochondria depend on mitochondrial subpopulation, brain region and age. Heavy mitochondria (HM) usually display the lowest content of respiratory components and the lowest enzymatic activities and it has been suggested that they represent the oldest mitochondrial population. In this study, we confirmed that HM are considerably compromised in their structure. In fact, HM showed to have the highest hydroperoxide content and the most consistent modifications in their fatty acid pattern with wide loss of fatty acids (or part of them) in the phospholipid moiety. Such situation could explain the typical impairment of HM and could support the hypothesis that they represent an old mitochondrial population.
    Free Radical Research 05/2002; 36(4):479-84. · 3.28 Impact Factor
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    ABSTRACT: The catalytic properties of energy-utilizing ATPases enzyme systems related to ions homeostasis were evaluated in different types of synaptic plasma membranes (SPM) and in somatic plasma membranes (SM) from cerebral cortex of rats aged 5, 10, and 22 months. The following enzymes were evaluated: Na+, K+-ATPase, Ca2+, Mg2+-ATPase, Mg2+-ATPase and the activity of acetylcholine esterase (AChE) was also evaluated. The ATPases located on SM and SPM and synaptic vesicles are involved in the regulation of presynaptic nerve ending homeostasis and postsynaptic activities. Different types of SM and SPM (three types) were obtained by combinations of differential and density gradient ultracentrifugation techniques in sucrose-Ficoll media: the first was obtained by purification of the sediment of mitochondrial supernate and the second after synaptosomal lysis and purification on density gradient. In the cerebral cortex of 5-month-old rats, the catalytic properties of ATPases systems markedly differ according to the different types of SPM and SM, thus indicating that the metabolic role of each ATPase is determined by their subcellular in vivo localization. As regards ageing: (i) ATPase enzyme catalytic activities tend to decrease during ageing in a complex way; (ii) ageing induced specific modifications in individual ATPases according to their subsynaptic localization; and (iii) these effects are probably due to specific biochemical situations that take place at each age, reflecting the bioenergetic state of the cerebral tissue with respect to the energy demand. The cerebral concentration and content of SM proteins were increased by ageing suggesting that many defective noncatalytic proteins may be formed during ageing, as shown by immunoblotting techniques.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 02/2002; 26(1):81-90. · 3.55 Impact Factor
  • A Gorini, R F Villa
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    ABSTRACT: The effects on energy-consuming ATP-ases were studied in two types of synaptic plasma membranes from rat cerebral cortex after in vivo injection of clonidine. To study the mechanism of action of clonidine at subcellular level, the enzyme activities of Na+, K+-ATP-ase, Ca2+, Mg2+-ATP-ase, Low- and High-affinity Ca2+-ATP-ase, and Mg2+-ATP-ase were evaluated on synaptic plasma membranes of control and treated animals with clonidine (5 microg x kg(-1); i.p. 30 minutes). Acute treatment with clonidine decreased the catalytic activity of Ca2+, Mg2+-ATP-ase and of low-affinity Ca2+-ATP-ase only in synaptic plasma membranes of II type, that is the fraction enriched in synaptic plasma membranes. The decreases of these enzymatic activities are related to the interference of the drug on Ca2+ homeostasis in synaptoplasm. The reductions of these enzyme-consuming ATP-ases give further evidence that clonidine has not only neuroreceptorial effects, but that the drug also affects the energy metabolism of cerebral tissue, improving the knowledges about the pharmacology of clonidine. Because the elevation of [Ca2+]i, during ischemia/hypoxia contributes to cellular injury, these findings may suggest that the prevention of calcium overload may be the key mechanism of protection by alpha2-agonist.
    Neurochemical Research 08/2001; 26(7):821-7. · 2.13 Impact Factor
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    ABSTRACT: Great attention has been devoted both to ageing phenomena at the mitochondrial level and to the antioxidant status of membrane structures. These kinds of investigations are difficult to perform in the brain because of its heterogeneity. It is known that synaptic heavy mitochondria (HM) may represent an aged mitochondrial population characterized by a partial impairment of their typical mitochondrial function. We arranged a novel system requiring no extraction procedure, very limited handling of the samples and their direct injection into the HPLC apparatus, to carry out, for the first time, a systematic and concomitant determination of vitamin E, Coenzyme Q9 (CoQ9) and Coenzyme Q10 (CoQ10) contents in rat brain mitochondria. The trends found for CoQ9 and CoQ10 levels in synaptic and non-synaptic occipital cerebral cortex mitochondria during rat ageing are consistent with previous data. Hydroperoxides (HP) differed with age and it was confirmed that in the HM fraction the summation of contributions results in an oxidatively jeopardized subpopulation. We found that vitamin E seems to increase with age, at least in non-synaptic free (FM) and synaptic light (LM) mitochondria, while it was inclined to remain substantially constant in HM.
    Biological Chemistry 07/2001; 382(6):925-31. · 2.96 Impact Factor

Publication Stats

1k Citations
341.15 Total Impact Points


  • 1977–2013
    • University of Pavia
      • Department of Molecular Medicine
      Ticinum, Lombardy, Italy
  • 2009
    • Istituto di Cura Città di Pavia
      Ticinum, Lombardy, Italy
  • 2003
    • Università Politecnica delle Marche
      Ancona, The Marches, Italy
  • 1988–1998
    • University of Catania
      • Department of Chemical Sciences
      Catania, Sicily, Italy
  • 1997
    • University of Bologna
      • Department of Biomedical Science and Neuromotor Sciences DIBINEM
      Bologna, Emilia-Romagna, Italy
  • 1978
    • Università degli Studi dell'Aquila
      • SS in Neurology
      Aquila, Abruzzo, Italy