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Background: Neurodegenerative and mood disorders represent growing medical and social problems, many of which are provoked by oxidative stress, disruption in the metabolism of various neurotransmitters, and disturbances in calcium homeostasis. Biologically active plant compounds have been shown to exert a positive impact on the function of calcium in the central nervous system., Methods: The present paper reviews studies of naturally occurring terpenes and derivatives and the calcium-based aspects of their mechanisms of action, as these are known to act upon a number of targets linked to neurological prophylaxis and therapy., Results: Most of the studied phytochemicals possess anticancer, antioxidative, anti-inflammatory, and neuroprotective properties, and these have been used to reduce the risk of or treat neurological diseases., Conclusion: The neuroprotective actions of some phytochemicals may employ mechanisms based on regulation of calcium homeostasis and should be considered as therapeutic agents.

Background: Balance in neurotransmission is essential for the proper functioning of the nervous system and even a small, but prolonged disturbance, can induce the negative feedback mechanisms leading to various neuropathologies. Neurodegenerative and mood disorders such as Alzheimer's, Parkinson's or affective disorders are increasing medical and social problems. Among the wide spectrum of potentially destructive events, oxidative stress and disrupted metabolism of some neurotransmitters such as acetylcholine, GABA, glutamate, serotonin or dopamine appear to play a decisive role. Biologically active plant polyphenols have been shown to exert a positive impact on the function of the central nervous system by modulation of metabolism and the action of some neurotransmitters., Methods: Based on published research, the pharmacological activities of some naturally occurring polyphenols have been reviewed, with a focus on their potential therapeutic importance in the regulation of neurotransmitter systems., Results: Phytochemicals can be classified into several groups and most of them possess anticancer, antioxidative, anti-inflammatory and neuroprotective properties. They can also modulate the metabolism or action of some neurotransmitters and/or their receptors. Based on these properties, phytochemicals have been used in traditional medicine for ages, although it was focused mainly on treating symptoms. However, growing evidence indicates that polyphenols may also prevent or slow neurological diseases., Conclusion: Phytochemicals seem to be less toxic than synthetic drugs and they can be a safer alternative for currently used preparations, which exert adverse side effects. The neuroprotective actions of some plant polyphenols in the regulation of neurotransmitters metabolism, functioning of neurotransmitters receptors and antioxidative defense have potential therapeutic applications in various neurodegenerative disorders., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Neurosteroids form the unique group because of their dual mechanism of action. Classically, they bind to specific intracellular and/or nuclear receptors, and next modify genes transcription. Another mode of action is linked with the rapid effects induced at the plasma membrane level within seconds or milliseconds. The key molecules in neurotransmission are calcium ions, thereby we focus on the recent advances in understanding of complex signaling crosstalk between action of neurosteroids and calcium-engaged events., Methods: Short-time effects of neurosteroids action have been reviewed for GABAA receptor complex, glycine receptor, NMDA receptor, AMPA receptor, G protein-coupled receptors and sigma-1 receptor, as well as for several membrane ion channels and plasma membrane enzymes, based on available published research., Results: The physiological relevance of neurosteroids results from the fact that they can be synthesized and accumulated in the central nervous system, independently from peripheral sources. Fast action of neurosteroids is a prerequisite for genomic effects and these early events can significantly modify intracellular downstream signaling pathways. Since they may exert either positive or negative effects on calcium homeostasis, their role in monitoring of spatio-temporal Ca2+ dynamics, and subsequently, Ca2+-dependent physiological processes or initiation of pathological events, is evident., Conclusion: Neurosteroids and calcium appear to be the integrated elements of signaling systems in neuronal cells under physiological and pathological conditions. A better understanding of cellular and molecular mechanisms of nongenomic, calcium-engaged neurosteroids action could open new ways for therapeutic interventions aimed to restore neuronal function in many neurological and psychiatric diseases., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

The primary function of angiotensin II, the main peptide of central renin-angiotensin system (RAS), is regulation of blood pressure. Recently, new functions of so-called local (or tissue) RAS have been discovered in brain. AT1 and AT2 angiotensin receptors, found in many parts of central nervous system (CNS), stimulate various signalling pathways. Gamma-amniobutyric acid (GABA), which acts by three types of receptors, is the crucial inhibitory neurotransmitter. GABA and angiotensins are found in brain regions like paraventricular nucleus of hypothalamus, nucleus tractus solitari and rostral ventrolateral medulla, all involved in blood pressure regulation. The influence of angiotensin II on GABA action is different in various CNS regions, but mainly it is associated with cardiovascular neurons activity. There are other neurotransmitters which may interact with angiotensins action. Adenosine has inhibitory effect and play important role in epilepsy. Its beneficial influence may be stronger in presence of angiotensin. Angiotensins also interact with dopamine (DA) activity by stimulation of DA-synthesizing nerves.

Calmodulin (CaM) is a sensor protein, which takes part in calcium-dependent signaling, regulating processes like growth, differentiation, proliferation and motility. Calmodulin binds calcium ions during induction of intracellular signaling. It is also involved in silencing of calcium signal through activation of plasma membrane Ca(2+)-ATPase (directly) or SERCA pump (indirectly). Calmodulin may affect various channels, e.g. voltage gated calcium channels (VGCCs), transient receptor potential channels (TRPCs), NMDA receptors, calcium channels dependent on cyclic nucleotides or these located in endoplasmic reticulum (ryanodine receptors and all isoforms of IP3-dependent receptors).

Introduction: The results of many studies have reported that peptides from the angiotensin family are involved in the regulation of cell growth, proliferation, cell migration, apoptosis, inflammation, differentiation, and angiogenesis, which suggests that they might play an important role in carcinogenesis. The role of the renin-angiotensin system in supporting prostate cancer induction and progression has so far received little study., Material and Methods: The present study was to examine the influence of Ang II, Ang III, and Ang IV on a human hormone-dependent prostate cancer line (LNCaP). Using an isotopic method, we tested the effects of angiotensins on tyrosine kinase activity, and measured cell viability using an MTT Assay., Results: The results showed that only Ang IV significantly reduced tyrosine kinase activity and cell viability in LNCaP cells. The process seemed to be mediated partly by AT(2) and probably by another type of receptor with high affinity for Ang IV and low affinity for PD123319 and Losartan., Conclusions: These findings suggest that components of the renin-angiotensin system, specifically angiotensin peptides and receptors (AT(1), AT(2)) can modify prostate cancer cell viability.

Background: Recently, the involvement of the renin-angiotensin system in the proliferation of prostate cancer has been suggested. There is increasing evidence that angiotensin II receptor type 1 (AT1) is expressed in a variety of cancer cells and tissues and may have a role in tumor growth, angiogenesis, and invasive activity of malignant lesions in vivo. The implications of data referring to an angiotensin receptor in hormone-independent human prostate cancer DU145 cells are unclear. Angiotensin II has been shown to inhibit the proliferation of DU145 cell lines. However, it is known that AT1 stimulates cell proliferation and that angiotensin II receptor type 2 (AT2) induces apoptosis and inhibits cell proliferation., Material/methods: The aim of our study was to investigate, by means of immunohistochemical and reverse transcriptase polymerase chain reaction assays, the type of angiotensin II receptor that is present in DU145 cells., Results: In DU145-derived complementary deoxyribonucleic acid (cDNA), a polymerase chain reaction assay revealed 2 AT1-specific PCR products (93 bp and 126 bp). DU145-derived cDNA did not reveal AT2 expression at a level sufficient for detection by PCR. In cultured cells, immunohistochemical testing revealed a positive reaction in cultures immunostained with anti-AT1 antibody but not in those immunostained with AT2 antibody., Conclusions: The inhibitory effect of angiotensin II on the proliferation of DU145 cells is exerted via AT1. It is possible that presence of 2 variants of AT1 in that cancer cell line is essential to produce the biological effects of angiotensin.

Gamma-aminobutyric acid is a major inhibitory neurotransmitter in the central nervous system. GABA metabolism is dependent on the activity of three enzymes: glutamic acid decarboxylase, GABA-transaminase and succinic semialdehyde dehydrogenase. Decreased activity of these enzymes may cause many neurological syndromes, such as stiff-person syndrome, chronic fatigue syndrome, anxiety disorders and seizures. This article is a review of most important problems related to an impairment of GABA metabolism.

Angiotensin 1-7 (Ang 1-7) is a peptide originated from Ang II. It is known that in vessels Ang 1-7 shows opposite effects to Ang II. Ang 1-7 can modify processes of proliferation. However, Ang 1-7 action in pituitary gland cells was never studied. Moreover, the specific binding sites for Ang 1-7 are still unknown. The aim of this study was to examine the effects of Ang 1-7 on tyrosine kinases (PTKs) activity in the anterior pituitary. The reaction of phosphorylation was carrying out in presence of different concentration of Ang 1-7 and losartan (antagonist of AT1 receptor) and PD123319 (antagonist of AT2). Our results show that Ang 1-7 inhibited activity of PTK to 60% of basic activity. Losartan did not change the Ang 1-7-induced changes in PTKs activity. The presence of PD123319 together with Ang 1-7 caused stronger inhibition PTKs activity than Ang 1-7 alone. These observations suggest that Ang 1-7 binds to the novel, unknown, specific for this peptide receptor.

Angiotensin III is the biological active peptide from the angiotensin family, which play the important role in several cellular processes. Ang III is the product of reaction catalyzed by aminopeptidase A and in turn can be a substrate for aminopeptidase N, enzyme which converts Ang III to shorter fragment, Ang IV. Aminopeptidase N is specifically inhibited by PC18. Ang III can act by binding to receptors AT1, AT2 or other type of receptors, which are not well recognized. The connection of Ang III to AT1 and AT2 receptors could be inhibited by losartan or PD123319, respectively. The aim of this study was to investigate what is the influence of angiotensin III on protein tyrosine kinase activity in rat pituitary and what is the possible place of interaction of Ang III with target cells. The obtained results show that Ang III can modify tyrosine kinase activity in concentration dependent manner but Ang IV appeared more effective. In presence of PC18 Ang III caused the same changes as Ang III alone that suggests that Ang III, not its metabolite modify tyrosine kinase activity. Losartan and PD123319 given together with Ang III enhanced the changes induced by Ang III. It suggests that the investigated peptide has an effect on protein tyrosine kinase activity in a different way than via AT1 and AT2 receptors.

Synapsins are the neuronal phosphoproteins which play very important role in processes of synaptic neurotransmission. They are physiological substrates for Ser/Thr protein kinases. The reversible phosphorylation of synapsins may be modified by several compounds including steroid hormones. The aim of our study was to investigate, if the one of neuroactive steroid--17beta-estradiol--could modulate the phosphorylation of synapsins by PKA, CaM-PK and PKC in rat brain and what type of mechanism of their action is possible. The activity of kinases was evaluated as phosphorylation of synapsin in cerebral cortex and hippocampus in vivo and in vitro conditions. We conclude that 17E2 has inhibitory effect on synapsins phosphorylation by all tested kinases in vitro and in vivo conditions. The lack of nuclei in synaptosomal membrane fraction and short time of hormone exposure can be evidence of direct, non-genomic mechanism of estradiol action.

Angiotensin II (Ang II) is known to modulate tyrosine kinases (PTKs) activity in pituitary tumor cells. It is known that AngII is acting via AT1 receptors in many tissues. The aim of this study was to see whether 3-8 fragment of AngII, called angiotensin IV (AngIV) has a similar effect on tyrosine kinase activity in normal pituitary gland and what type of angiotensin receptor is involved in this process. The homogenates of normal rat pituitaries was a source of enzymes. The PTKs activity was determined using the synthetic substrate poly GluTyr and gamma-(32)P-ATP. Ang IV was found to increase the PTK activity in the rat anterior pituitary tissue, with the maximal effect at concentration of 10(-10) M. AngII was ineffective at all concentrations studied. Losartan, a selective AT1 receptor blocker, added together with Ang IV abolished the effect of the latter, however losartan diminished also the PTK activity when applied together with Ang II, but only when it was added immediately before, but not after, the addition of Ang II. The involvement of a non-classic AT1-like receptor is suggested.

Objectives: The present study was designed to test whether various steroid hormones modulate differently angiotensin II (AngII) action in the anterior pituitary in males and females., Material and Methods: Adult female and male rats were treated with one of the following substances: oil (control), pregnenolone sulfate (PREG-S), 17beta-estradiol benzoate (E2,) progesterone (P), or dehydroepiandrosterone sulfate (DHEA-S), given in intraperitoneal injections for five days in dose of 50 microg per animal per day. Because AngII is known to act in the anterior pituitary through the phosphatidiloinositol breakdown, thus increasing the level of inositol-1,4,5-trisphosphate (IP3), the IP3 concentration was determined 24 hours after the injection in the anterior pituitary homogenate exposed to AngII., Results: In control animals (without steroids) AngII stimulated concentration of IP(3) stronger in females than in males. E(2) and DHEA-S enhanced AngII effects in both males and females. PREG-S increased AngII-induced IP(3) concentration in females, but not males. Progesterone raised AngII effect on IP(3) concentration in males, only when high concentrations of peptide were used., Conclusion: These results indicate that pituitary sensitivity to AngII stimulation is modulated by steroid hormones and is related to the gender of the animal.

The effects of angiotensin II (AngII) and its fragment 3-8 (angiotensin IV, AngIV) on tyrosine kinase (TK) activity in estrogen-induced rat pituitary tumor homogenates were studied. It was found that both angiotensin peptides increase the TK activity. AngIV was effective in a lower concentration and its maximal effect was greater as compared to that of AngII. Moreover, the specific inhibitors of aminopeptidase A (EC33) and of aminopeptidase N (PC18) significantly attenuated the stimulatory effect of AngII. Because the action of both aminopeptidases is necessary to convert AngII into AngIV, this finding suggested that the effect of AngII on TK activity is (at least in part) exerted via AngIV.

To investigate whether the various steroid hormones can modulate the basal and angiotensin II-induced protein kinase C (PKC) activity in the anterior pituitary of the rat, female and male intact and ovariectomized female Wistar rats were treated in vivo with estradiol (E2), progesterone (P), dehydroepiandrostendione sulfate (DHEA-S), and pregnenolone sulfate (PREG-S). Estradiol caused the increase of basal PKC activity in intact and ovariectomized females, but did not change the enzyme activity in males. In ovariectomized animals the increase of PKC activity was lower than in intact females. Progesterone decreased PKC activity only in intact animals. DHEA-S strongly enhanced activity of PKC in ovariectomized females. Pregnenolone sulfate did not significantly change PKC function of all studied groups. Incubation with AngII enhanced the PKC activity in intact (without steroid treatment) animals of both genders. In females, AngII and estradiol together rise the PKC-stimulated phosphorylation in greater degree than used separately. Treatment with other investigated steroids reduced the effect of AngII. In intact males every examined hormone turned back the stimulatory effect of AngII on PKC activity. These data suggest that gender differences in PKC activity are likely related to hormonal milieu of experimental animals and may depend in part on the basic plasma level of estrogens.

The present study was designed to test whether pregnenolone sulfate can influence the angiotensin II (AngII) action in the anterior pituitary. Female rats were ovariectomized and 10 days after operation were treated with either 50 or 250 microg per animal in one of the following substances: oil (control), pregnenolone sulfate (PREG-S), estradiol benzoate (E(2),) progesterone (P), or dehydroepiandrosterone sulfate (DHEA-S), given in single intraperitoneal injection. Because AngII is known to act in the anterior pituitary through the phosphatidiloinositol breakdown, thus increasing the level of inositol-1,4,5-trisphosphate (IP(3)), the IP(3) concentration was determined 24 h after the injection in the anterior pituitary homogenate after in vitro exposure to AngII. Among the tested steroids only PREG-S enhanced the basal (without AngII) and AngII-induced level of IP(3) in both doses used. There was no difference between the effect of a high and low dose of PREG-S. These results show that PREG-S may modulate AngII action in the anterior pituitary, regardless of the presence of ovary., (Copyright 2001 Academic Press.)

Background: Protein phosphorylation plays a very important role in the modulation of signal transduction in many tissues including heart. The activities of protein tyrosine kinases (PTKs) of the heart are rather low but PTKs in cardiac myocytes could be involved in many processes including necrosis, apoptosis, and inflammation. All of them lead to heart failure and are the result of such conditions as ischemia and reperfusion. The aim of our study was to investigate if the ischemia and reperfusion could change the protein tyrosine kinases activities in rat cardiac myocytes., Material and Methods: The specific activities of PTKs were defined as (3)2P incorporation into exogenous poly(Glu, Tyr)--known as an artificial substrate for all types of protein tyrosine kinases., Results: The activity of tyrosine kinases in ischemic heart was lower than in control-intact heart and amounted to 50-60% of control values. In the heart after ischemia and following reperfusion the activities of PTKs increased to 135% of control., Conclusions: Ischemia and reperfusion changed activity of PTKs. There were no differences in protein tyrosine activity between the left and right ventricles.

The effects of native somatostatin-14 (SS-14) and of its two analogues, octreotide and CH-275, on the activity of tyrosine kinases (TK) in two rodent tumors (rat pituitary tumor and murine colonic cancer) were studied in vitro. The activity of TK was measured in tissue homogenates using gamma[(32)P]ATP as the donor of the phosphoryl group and poly(Glu(80), Tyr(20)) as a substrate. It was found that native SS-14 inhibited TK activity in both investigated tumors. Octreotide, which acts preferentially via somatostatin receptor subtype 2 (SSTR2), was very effective in inhibiting TK activity in the rat pituitary tumor, but it is a rather weak inhibitor of TK activity in murine colonic cancer. CH-275, a selective ligand of the SSTR1 subtype of SS receptors, suppressed TK activity in the pituitary tumor but was ineffective in the colonic cancer. It is hypothesized that the effect of neuropeptide somatostatin (SS-14) on murine colonic cancer is exerted via the subtype of receptor which does not interact with CH-275 and has no or low affinity for octreotide (SSTR 4, 3 or 5?)., (Copyright 2000 S. Karger AG, Basel.)

Angiotensin II (AngII) is known to act in the anteriorpituitary through phosphatidiloinositol breakdown, increasing the level of inositol-1,4,5-trisphosphate (IP(3)) and diacyloglycerol (DAG), a potential activator of protein kinase C (PKC). We examined the effect of estradiol and progesterone treatment in vivo on IP(3) levels and activity of PKC under the influence of AngII. Three groups of intact female rats received in vivo injections of 17-beta-estradiol, progesterone, and oil (control) for five days, and then the in vitro effect of AngII was examined using homogenate of the anterior pituitary. AngII increased either the IP(3) concentration or the synapsin I phosphorylation catalyzed by PKC. Estradiol enhanced the basal (without AngII) IP(3) level and PKC activity induced by AngII. Progesterone did not change the basal and AngII-induced IP(3) concentrations. On the other hand, it decreased the basal PKC activity and blocked the effect of AngII. Our data suggest that ovarian steroids can modulate the effect of AngII on the anterior pituitary gland., (Copyright 2000 Academic Press.)

The present study was undertaken to investigate the effect of angiotensin II (AngII) on the concentration of inositol-1,4,5-trisphosphate (IP3) and the modulation of AngII action by estradiol in the brain. Our studies were conducted in male rat anterior pituiary, hypothalamus and cerebral cortex with and without previous estradiol treatment. In the cerebral cortex, there were no changes in IP3 content after exposure to AngII. In the anterior pituitary, AngII increased the IP3 concentration at all doses studied. However, in the hypothalamus, AngII decreased the IP3 concentration and its effect was also time dependent. Prior treatment with estradiol intensified the effects of AngII action on IP3 concentrations, in both the pituitary (increase) and hypothalamus (decrease). These results indicate that in the male rat anterior pituitary, AngII increases phosphatidiloinositol hydrolysis, leading to the increased production of the intracellular messenger, IP3. The decrease of IP3 concentration observed in the hypothalamus suggests a different site of AngII action in this region. We also suggest that estrogens can modulate AngII action in the brain.