R F Villa

University of Pavia, Ticinum, Lombardy, Italy

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Publications (139)387.52 Total impact

  • Antonio Moretti · Federica Ferrari · Roberto F Villa
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    ABSTRACT: 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. Copyright © 2015. Published by Elsevier Inc.
    No preview · Article · Jun 2015 · Pharmacology [?] Therapeutics
  • Federica Ferrari · Antonella Gorini · Roberto Federico Villa
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    ABSTRACT: Synaptic energy state and mitochondrial dysfunction are crucial factors in many brain pathologies. L-acetylcarnitine, a natural derivative of carnitine, improves brain energy metabolism, and has been proposed for the Therapy of many neurological and psychiatric diseases. The effects of the drug on the maximum rate (Vmax) of enzymatic activities related to hippocampal synaptic energy utilization were evaluated, in the perspective of its employment for Dementias and Depression Therapy. Two types of synaptic plasma membranes (SPM1 and SPM2) were isolated from the hippocampus of rats treated with L-acetylcarnitine (30 and 60mg/kg i.p., 28 days, 5 days/week). Acetylcholinesterase (AChE); Na(+), K(+), Mg(2+)-ATP-ase; ouabain-insensitive Mg(2+-)ATP-ase; Na(+), K(+)-ATP-ase; Ca(2+), Mg(2+)-ATP-ase activities were evaluated. In control animals, enzymatic activities were differently expressed in SPM1 respect to SPM2, being the evaluated enzymatic activities higher in SPM2. Subchronic treatment with L-acetylcarnitine (i) did not modify AChE on both SPMs; (ii) increased Na(+), K(+), Mg(2+) ATP-ase, ouabain-insensitive Mg(2+) ATP-ase and Na(+), K(+) ATP-ase at the dose of 30 and 60mg/kg on SPM1 and SPM2; (iii) increased Ca(2+), Mg(2+)-ATP-ase activity on both SPMs at the dose of 60mg/kg. These results have been discussed considering the pathophysiology and treatment of Dementias and Depression because, although referred to normal healthy animals, they support the notion that L-acetylcarnitine may have positive effects in these pathologies. Copyright © 2015. Published by Elsevier B.V.
    No preview · Article · Mar 2015 · European journal of pharmacology
  • Federica Ferrari · Antonella Gorini · Roberto Federico Villa
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    ABSTRACT: Functional proteomics was used to characterize age-related changes in energy metabolism of different neuronal pathways within the cerebellar cortex of Wistar rats aged 2, 6, 12, 18, and 24 months. The "large" synaptosomes, derived from the glutamatergic mossy fibre endings which make synaptic contact with the granule cells of the granular layer, and the "small" synaptosomes, derived from the pre-synaptic terminals of granule cells making synaptic contact with the dendrites of Purkinje cells, were isolated by a combined differential/gradient centrifugation technique. 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. This study represents a reliable model to study in vivo (1) the physiopathological molecular mechanisms of some brain diseases dependent on energy metabolism, (2) the responsiveness to noxious stimuli, and (3) the effects of drugs, discriminating their action sites at subcellular level on specific neuronal pathways.
    No preview · Article · Nov 2014 · Neurochemical Research
  • 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.
    No preview · Article · Sep 2014 · Pharmacology [?] Therapeutics
  • Roberto F Villa · Federica Ferrari · Antonella Gorini
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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.
    No preview · Article · Nov 2013 · Journal of Proteome Research
  • Roberto Federico Villa · Antonella Gorini · Federica Ferrari · Siegfried Hoyer
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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.
    No preview · Article · Oct 2013 · Neurochemistry International
  • 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.
    No preview · Article · Jun 2013 · Neuroscience
  • 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.
    No preview · Article · Oct 2012 · Neurochemistry International
  • 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.
    No preview · Article · Sep 2012 · Neuroscience
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    Roberto Federico 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.
    Full-text · Article · Jan 2012 · Neural Regeneration Research
  • 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+, Mg2+-ATP-ase; ouabain insensitive Mg2+-ATP-ase; Na+, K+-ATP-ase; direct Mg2+-ATP-ase; Ca2+, Mg2+-ATP-ase; Low- and High-affinity Ca2+-ATP-ase. Sub-chronic treatment with l-acetylcarnitine increased Na+, K+-ATP-ase activity on SPM 2 and Ca2+, Mg2+-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.
    No preview · Article · Apr 2011 · Neurochemical Research
  • 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.
    No preview · Article · Feb 2011 · CNS & neurological disorders drug targets
  • R.F. Villa · A. Gorini
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    ABSTRACT: The maximum rates (Vmax) of some mitochondrial enzymatic activities related to energy transduction such as citrate synthase, succinate dehydrogenase, malate dehydrogenase for Krebs' cycle; NADH-cytochrome c reductase (both total and rotenone sensitive), succinate CoQ reductase, succinate cytochrome c reductase, cytochrome oxidase, for the electron transfer chain (ETC); glutamate dehydrogenase, glutamate-pyruvate-transaminase, glutamate-oxaloacetate-transaminase for glutamate and aminoacids metabolism were evaluated in non-synaptic and intra-synaptic mitochondria from cerebral cortex of Macaca fascicularis (Cynomolgus monkey). These three types of mitochondria were isolated from dopaminergic terminals of monkey's cerebral cortex after a Parkinson's Disease like syndrome induced by e.v. injections of MPTP neurotoxin. In control (vehicle-treated) animals, the biochemical machinery is differently expressed in non-synaptic mitochondria with respect to "light" and "heavy" intra-synaptic ones and also between intra-synaptic themselves. The activities of citrate synthase, succinate dehydrogenase, malate dehydrogenase, NADH-cytochrome c reductase, succinate cytochrome c reductase, glutamate dehydrogenase and glutamate-pyruvate- and glutamate-oxaloacetate- transaminases are lower, while cytochrome oxidase is higher in intra"synaptic -light" and "heavy" mitochondria than those in non"synaptic ones, being succinate cytochrome c reductase activity the same in all mitochondria types. Some enzyme activities are lower in "heavy" than in "light" intra-synaptic mitochondria, confirming that in various types of brain mitochondria also from primates, a different metabolic machinery exists, due to their different location in vivo, in soma or synapses. In the MPTP-treated animals (Parkinson's like syndrome), the systemic treatment with the neurotoxin (i.v., 0.3 mg/kg/day for 5 days) increased the activity of succinate dehydrogenase and succinate CoQ reductase only in "light" intra-synaptic mitochondria (decreasing the glutamate dehydrogenase activity) and the neurotoxin decreased also cytochrome oxidase activities in all mitochondria types and that of glutamate-pyruvate-transaminase of non-synaptic mitochondria. Thus, MPTP stimulated the succinate metabolism, increasing the activity of Complex II, but decreasing the activity of Complex IV, the most sensitive Complex to neurotoxin, not affecting the activities of Complex I, Complex I-III, Complex II-III; also glutamate metabolism is affected by MPTP, decreasing the activity of glutamate dehydrogenase ("light" intra-synaptic mitochondria) and particularly that of glutamate-pyruvate-transaminase on non-synaptic mitochondria. The data on functional proteomics of these different types of mitochondria suggest that the treatment with MPTP, as a model of Parkinson's Disease, affected the activities linked mainly to succinate metabolism of "light" intra-synaptic mitochondria, instead of Complex I, as previously hypothesized, indicating that the link between the Krebs' cycle and ETC seems to be of primary pathogenetic significance, indicating a specific subcellular trigger site of action. These results presented in this chapter also suggest a specific molecular trigger mode of action on energy metabolism of cerebral dopaminergic terminals, being the neurotoxin effective also on enzyme activities of non-synaptic mitochondria for transamination of pyruvate, while Complex IV activity was already decreased by MPTP, thus impairing the ATP synthesis in any case.
    No preview · Article · Jan 2011
  • Roberto Federico Villa · Federica Ferrari · Antonella Gorini

    No preview · Conference Paper · Jan 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.
    Full-text · Article · Jul 2009 · Membrane biochemistry
  • 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 (V max) 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.
    No preview · Article · Jul 2009 · Neurochemical Research
  • 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.
    No preview · Article · Dec 2006 · Journal of Neural Transmission
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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.
    Preview · Article · Oct 2003 · Molecular Psychiatry
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    ABSTRACT: Neurodegenerative Diseases represent the most commmon 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 ϵ4 allele in control group was estimated, against 15.8% observed in patients. The frequency of ϵ2 and ϵ3 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 ϵ3/ϵ3 genotype and ϵ3/ϵ4 genotype in the control group compared to patients' group. The frequencies observed in ϵ2/ϵ3 genotype groups were 8.7% vs 15.8% and of e2/e4 genotype 17.4% vs 5.3%. The ϵ2/ϵ2 and ϵ4/ϵ4 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.
    No preview · Article · Jan 2003 · BioFactors
  • 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.
    No preview · Article · Oct 2002 · Neurochemical Research

Publication Stats

2k Citations
387.52 Total Impact Points

Institutions

  • 1975-2015
    • University of Pavia
      • Department of Molecular Medicine
      Ticinum, Lombardy, Italy
  • 2009
    • Istituto di Cura Città di Pavia
      Ticinum, Lombardy, Italy
  • 1988-1996
    • University of Catania
      • Department of Chemical Sciences
      Catania, Sicily, Italy
  • 1978
    • Università degli Studi dell'Aquila
      • SS in Neurology
      Aquila, Abruzzo, Italy