Walther Bild

Changes of some oxidative stress markers in the serum of patients with mild cognitive impairment and Alzheimer's disease.

Mild cognitive impairment (MCI) is a nosological entity proposed as an intermediate state between normal aging and dementia. MCI seems to represent an early stage of Alzheimers disease (AD) and there is a great interest in the relationship between MCI and the progression to AD. Some studies have demonstrated an accumulation of products of free radical damage in the central nervous system and in the peripheral tissues of subjects with AD or mild cognitive impairment. The aim of the present work was to evaluate the serum levels of some enzymatic antioxidant defences like superoxide dismutase (SOD) and glutathione peroxidase (GPX), as well as lipid peroxidation markers like MDA (malondialdehyde), in MCI and AD patients, compared with age-matched healthy controls. The subjects of this study (45 patients) consisted of 15 individuals with mild cognitive impairment (MCI), 15 with Alzheimers disease (AD) and 15 healthy age-matched controls. Biochemical analyses showed a similar decrease of the main enzymatic antioxidant defences (SOD and GPX) and increased production of lipid peroxidation marker (MDA) in the serum of the MCI and AD patients, compared to age-matched control group. This study clearly demonstrates that oxidative stress damage occurs in patients with MCI and AD. Moreover, some enzymatic markers of oxidative stress are similar in MCI and AD patients, suggesting that oxidative damage could be one important aspect for the onset of AD.

Angiotensin peptides and their pleiotropic actions

The concept of tissue renin-angiotensin systems (RAS) is now well established and it is now usual to think in terms of renal and tissue systems. At the same time it has emerged that angiotensin II (Ang II) is not the only biologically active peptide generated by the RAS. At least three others have been identified: the heptapeptide Ang III, the hexapeptide Ang IV and Ang 1-7. Specific receptors exits for the last two peptides. In addition, the range of possible physiological and pathophysiological properties for Ang II„ has been expanding. The current perception of the RAS is therefore that of a much more complex system than previously believed, with autocrine, paracrine and endocrine properties extending beyond the cardiovascular system. This mini-review focuses on the synthetic pathways of the Ang peptides and describes some of their pleiotropic actions.

Inhibition of central angiotensin II enhances memory function and reduces oxidative stress status in rat hippocampus.

While it is now well established that the independent brain renin-angiotensin system (RAS) has some important central functions besides the vascular ones, the relevance of its main bioactive peptide angiotensin II (Ang II) on the memory processes, as well as on oxidative stress status is not completely understood. The purpose of the present work was to evaluate the effects of central Ang II administration, as well as the effects of Ang II inhibition with either AT1 and AT 2 receptor specific blockers (losartan and PD-123177, respectively) or an angiotensin-converting enzyme (ACE) inhibitor (captopril). These effects were studied on the short-term memory (assessed through Y-maze) or long-term memory (as determined in passive avoidance) and on the oxidative stress status of the hippocampus. Our results demonstrate memory deficits induced by the administration of Ang II, as showed by the significant decrease of the spontaneous alternation in Y-maze (p=0.015) and latency-time in passive avoidance task (p=0.001) when compared to saline. On the other side, the administration of all the aforementioned Ang II blockers significantly improved the spontaneous alternation in Y-maze task, while losartan also increased the latency time as compared to saline in step-through passive avoidance (p=0.042). Also, increased oxidative stress status was induced in the hippocampus by the administration of Ang II, as demonstrated by increased levels of lipid peroxidation markers (malondialdehyde-MDA concentration) (p<0.0001) and a decrease in both antioxidant enzymes determined: superoxide dismutase-SOD (p<0.0001) and glutathione peroxidase-GPX (p=0.01), as compared to saline. Additionally, the administration of captopril resulted in an increase of both antioxidant enzymes and decreased levels of lipid peroxidation (p=0.001), while PD-123177 significantly decreased MDA concentration (p>0.0001) vs. saline. Moreover, significant correlations were found between all of the memory related behavioral parameters and the main oxidative stress markers from the hippocampus, which is known for its implication in the processes of memory and also where RAS components are well expressed. This could be relevant for the complex interactions between Ang II, behavioral processes and neuronal oxidative stress, and could generate important therapeutic approaches.

Angiotensin-(1–7) central administration induces anxiolytic-like effects in elevated plus maze and decreased oxidative stress in the amygdala

There is increasing evidence that besides the well-known angiotensin (Ang) II, other renin-angiotensin system (RAS) peptides, including Ang-(1-7), could have important effects at the central level. However, very few things are known about the central actions of Ang-(1-7), while the effects of its administration alone on anxiety have not been tested to date, to the best of our knowledge. In this way, we were interested in studying the effects of Ang-(1-7) intracerebroventricular administration on anxiety levels, as studied through some main behavioral parameters in the elevated plus maze, as well as the importance of Ang-(1-7) in the oxidative stress status from the amygdala, which is one of the key brain regions involved in mediating anxiety. We report here a possible anxiolytic-like effect of Ang-(1-7) administration, as demonstrated by the increased percentage of time spent and frequency of entries in the open arms of the elevated plus maze, as well as increased head-dipping behavior in the open arms and decreased stretching in closed arms. Also some antioxidant effects of Ang-(1-7) are suggested since a significant increase of GPX specific activity and a decrease of the main peroxidation marker MDA were observed in the amygdala. Moreover, we found a significant correlation between most of the behavioral parameters in the elevated plus maze and the levels of the oxidative stress markers. However, further studies are necessary in order to elucidate the effects of Ang-(1-7) administration on anxiety and oxidative stress status and also on the possible correlation that might exists between these aspects.

Effects of angiotensin II receptor antagonists on anxiety and some oxidative stress markers in rat

In addition to its known classical roles, the renin angiotensin system (RAS) has more subtle functions which include the regulation of emotional responses. Previous studies regarding the anxiety related behavior of RAS have showed controversial results. There is also evidence that oxidative stress accompanies angiotensin II infusion, but the role of AT1/AT2 specific receptors is not clear. The aim of this study was to evaluate the effects of central angiotensin II receptor blockers on anxiety state and oxidative stress. Behavioral testing included elevated plus maze, while oxidative stress status was measured though the extent of a lipid peroxidation product (malondialdehyde-MDA) and the specific activity of some defense antioxidant enzymes (superoxide dismutase-SOD and glutathione peroxidase-GPx). The rats treated with angiotensin II spent significantly less time in the open-arms of elevated-plus-maze, while the administration of losartan resulted in a significant increase of this time. We observed a significant increase of MDA concentration in the angiotensin II group and a decrease of MDA levels in both losartan and PD-123177 groups. In addition, a significant correlation was seen between the time spent in the open arms and oxidative stress markers. These findings could lead to important therapeutic aspects regarding the use of angiotensin II receptor blockers in anxiety-related disorders.

The interdependence of the reactive species of oxygen, nitrogen, and carbon.

This mini-review tries to summarize the main interdependences between the free radicals of oxygen, nitrogen, and carbon. Also, the main metabolic pathways for these radical species are described, as well as how these affect their interaction and functional implications. Emphasis is made on the metabolic disturbances induced by stressing aggressions that produce radical species. In this way, cellular oxidative imbalances created by the superiority of reactive oxygen species over the antioxidant systems produce both activation of nitroxide synthases and the oxidation of terminal nitrogen from l-arginine, as well as the metabolization of heme until carbon monoxide by nitric oxide-activated hemoxygenase. Also, multiple cellular protein and nucleoprotein alterations determined by these three kinds of radical species are completed by the involvement of hydrogen sulfide, which results from the degradation of l-cysteine by cistationine-γ-lyase. In this way, sufficient experimental data tend to demonstrate the involvement of hydrogen sulfide and other thiol derivatives in the interrelations between oxygen, nitrogen, and carbon, which results in a true radical cascade. Thus, oxidative stress, together with nitrosative and carbonilic stress, may constitute a central point where other factors of vulnerability meet, and their interactions could have an important impact in many modern diseases. Considering that the actions of reactive species can be most of the time corrected, future studies need to establish the therapeutical importance of various agents which modulate oxidative, nitrosative, or carbonilic stress.

Inhibition of Central Angiotensin Converting Enzyme Exerts Anxiolytic Effects by Decreasing Brain Oxidative Stress

Inhibition of Central Angiotensin Converting Enzyme Exerts Anxiolytic Effects by Decreasing Brain Oxidative Stress This study investigated the effects of angiotensin II and captopril intracerebroventricular administration on anxiety status and brain oxidative stress. Elevated plus maze was used in order to asses the anxiety-like behavior, while the biochemical analysis included the determination of some antioxidant defense enzymes like superoxide dismutase and glutathione peroxidase and also a lipid peroxidation product (malondialdehyde). Our results provide additional evidence of angiotensin II induced anxiety-like effects and increased prooxidant status. Moreover, the blockade of angiotensin II, by the administration of an angiotensin converting enzyme inhibitor (captopril) resulted in anxiolytic effects and decreased oxidative stress status. In addition, we found a significant correlation between the time spent by rats in the open arms of the elevated plus maze and oxidative stress markers. This could raise important therapeutic issues regarding the anxiolytic effects of some angiotensin converting enzyme inhibitors used primarily for hypertension, such as captopril. Also, it seems that oxidative stress could play an important part in these actions. Inhibicija Centralnog Enzima Koji Konvertuje Angiotenzin Deluje Kao Anksiolitik Smanjujući Oksidativni Stres u Mozgu Ispitivan je uticaj intracerebroventrikularne administracije angiotenzina II i kaptoprila na napetost i oksidativni stres u mozgu. Za procenjivanje ponašanja bliskog anksioznosti korišćen je test uzdignutog lavirinta u obliku znaka plus, dok je biohemijska analiza obuhvatila određivanje nekih enzima antioksidantne odbrane kao što su superoksid-dismutaza i glutation-peroksidaza i proizvoda lipidne peroksidacije (malondialdehid). Naši rezultati predstavljaju još jedan dokaz da angiotenzin II izaziva posledice nalik na anksioznost i povišen prooksidantni status. Štaviše, blokiranje angiotenzina II davanjem inhibitora enzima koji konvertuje angiotenzin (kaptoprila) delovalo je kao anksiolitik i dovelo do sniženja statusa oksidativnog stresa. Pored toga, otkrivena je značajna korelacija između vremena koje su pacovi proveli u otvorenim »rukama« lavirinta i markera oksidativnog stresa. Ovo možda ukazuje na važnost pokretanja nekih važnih terapijskih pitanja koja se tiču anksiolitičkog dejstva nekih inhibitora enzima koji konvertuju angiotenzin a koji se pre svega koriste za hipertenziju, kakav je kaptopril. Takođe, sva je prilika da oksidativni stres u tome igra važnu ulogu.

Biphasic effects of angiotensin (1-7) and its interactions with angiotensin II in rat aorta

Using isolated rat aortic rings perfused with Krebs-Henseleit saline, the vascular effects of angiotensin (1-7) (Ang [1-7]) and its interactions with angiotensin II (Ang II) were investigated. Ang (1-7) induced endothelium-dependent relaxation and vasodilating effects in preparations precontracted with phenylephrine. Without preconstriction, Ang (1-7) at high doses (10 -6—10-5 M) produced either a significant inhibition of Ang IIinduced vasoconstriction or a non-tachyphylactic vasopressor response. While losartan inhibited the vasoconstriction induced by Ang (1-7), A779 blocked only its relaxation. Unlike losartan, blockade of AT2-receptors with PD 123319 had no effect. Taking into account the biphasic effects of angiotensin (1-7), we propose that it is one of the active components of the renin-angiotensin system, which is involved as a modulator both in the counter-regulatory actions of Ang II and in the self-regulation of its own vasodilating effects.

Aspects Regarding the Neurobiology of Psycho-Affective Functions

Aspects Regarding the Neurobiology of Psycho-Affective Functions In this mini-review we were interested in analyzing the main achievements concerning the neurobiological substrate of the human psycho-affective functions. The cortico-subcortical areas implicated in the elaboration and the control of the sensorial and psycho-affective reactions of the human brain are described, as well as the neurobiological basis of the psychic and affective manifestations, with focus on the new achievements in understanding the genetic, morpho-chemical and electromagnetic bases of the psycho-affective and behavioral manifestations, both normal and pathological. It is known that emotional states like anxiety, fear or anger generate complex psycho-affective reactions that are controlled by the limbic system, which is called the emotional brain. This is connected with the polyneuronal circuits of the Papez loop, the hypothalamic-pituitary complex and the reticular formation of the brainstem. Some imagistic aspects concerning the implication of the amygdala and the cingulate gyrus in laughing and crying are mentioned, as well as the cerebral areas implicated in romantic and maternal love. Also, some electromagnetic manifestations of the brain are presented, introducing the concept of «electromagnetic plasma», as a possible component of the human brain activity. Aspekti Koji se Tiču Neurobiologije Psihičko-Afektivnih Funkcija Naš interes u ovom mini pregledu bio je da analiziramo glavna dostignuća vezana za neurobiološki supstrat humanih psihičko-afektivnih funkcija. Opisana su kortiko-supkortikalna područja uključena u elaboraciju i kontrolu senzornih i psihičko-afektivnih reakcija u ljudskom mozgu, kao i neurobiološka osnova psihičkih i afektivnih manifestacija, uz poseban osvrt na nova dostignuća u razumevanju genetskih, morfo-hemijskih i elektromagnetskih osnova psihičko-afektivnih i bihevioralnih manifestacija, kako normalnih, tako i patoloških. Poznato je da emocionalna stanja poput anksioznosti, straha ili besa stvaraju složene psihičkoafektivne reakcije koje kontroliše limbički sistem, koji se još naziva emocionalnim mozgom. Ovo je povezano s polineuronalnim kolima Papezovog kruga, kompleksom hipotalamus-hipofiza i retikularnom formacijom moždanog stabla. Navedeni su neki aspekti slikovne dijagnostike koji se tiču učešća amigdale i gyrus cingulatus-a u smejanju i plakanju, kao i cerebralnih područja koja imaju ulogu u romantičnoj i majčinskoj Ijubavi. Takođe su predstavljene neke elektromagnetske manifestacije mozga, uz uvođenje koncepta «elektromagnetske plazme», kao moguće komponente aktivnosti Ijudskog mozga.

P02-170 Comparative effects of captopril, losartan and PD123319 on the memory processes in rats

Aims Renin-angiotensin system in the central nervous system participates in the processing of sensory information, learning and memory processes. Inhibitors of renin-angiotensin system, particularly angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists are reported to have potential effects in various learning and memory processes. In the present study we assessed the effects of angiotensin converting enzyme inhibitor captopril and the angiotensin AT1 receptors antagonists, lostartan and PD123319, in learning and memory processes by means of Y-maze and passive avoidance tasks. The anxiety state was measured in elevated plus maze. Methods Male Wistar rats were divided into three groups: 1. sham-operated; 2. Captopril; 3. Losartan; 4. PD123319. All drugs were stereotaxically icv injected, rather than captopril (i.p.). Learning and memory tests began 2 weeks after the operation, and the ability of the rats to acquire the operant task was studied by means of Y-maze task and passive avoidance task, respectively. The anxiety state was measured in elevated plus maze. Results Captopril, losartan and PD123319 significantly impaired spatial memory in Y-maze task, suggesting significant effects on short-term memory. In passive avoidance task, all drugs, significantly decreased step-through-latency, suggesting significant effects on long-term memory. In elevated plus maze measuring anxiety, all drugs diminished anxiety state. Conclusions These results suggest the involvement of the brain renin-angiotensin system in learning and memory formation.