Thymus atlanticus: A Source of Nutrients with Numerous Health Benefits and Important Therapeutic Potential for Age-Related Diseases.

Thymus atlanticus (Lamiaceae) is a plant endemic to the Mediterranean basin that is found in significant quantities in the arid regions of Morocco. Thymus atlanticus is used in traditional medicine to treat infectious and non-infectious diseases. It is also used for the isolation of essential oils and for the seasoning of many dishes in the Mediterranean diet. The major constituents of Thymus atlanticus are saponins, flavonoids, tannins, alkaloids, various simple and hydroxycinnamic phenolic compounds, and terpene compounds. Several of these compounds act on signaling pathways of oxidative stress, inflammation, and blood sugar, which are parameters often dysregulated during aging. Due to its physiochemical characteristics and biological activities, Thymus atlanticus could be used for the prevention and/or treatment of age-related diseases. These different aspects are treated in the present review, and we focused on phytochemistry and major age-related diseases: dyslipidemia, cardiovascular diseases, and type 2 diabetes.

Cell Penetrating Peptides Used in Delivery of Therapeutic Oligonucleotides Targeting Hepatitis B Virus.

Peptide Nucleic Acid (PNAs) and small noncoding RNAs including small interfering RNAs (siRNAs) represent a new class of oligonucleotides considered as an alternative therapeutic strategy in the chronic hepatitis B treatment. Indeed, chronic hepatitis B virus (HBV) infection remains a major public health problem worldwide, despite the availability of an effective prophylactic vaccine. Current therapeutic approaches approved for chronic HBV treatment are pegylated-interferon alpha (IFN)-α and nucleos(t)ide analogues (NAs). Both therapies do not completely eradicate viral infection and promote severe side effects. In this context, the development of new effective treatments is imperative. This review focuses on antiviral activity of both PNAs and siRNAs targeting hepatitis B virus. Thus, we briefly present our results on the ability of PNAs to decrease hepadnaviral replication in duck hepatitis B virus (DHBV) model. Interestingly, other oligonucleotides as siRNAs could significantly inhibit HBV antigen expression in transient replicative cell culture. Because the application of these oligonucleotides as new antiviral drugs has been hampered by their poor intracellular bioavailability, we also discuss the benefits of their coupling to different molecules such as the cell penetrating peptides (CPPs), which were used as vehicles to deliver therapeutic agents into the cells.

Transforming growth factor-ß1 induces cerebrovascular dysfunction and astrogliosis through angiotensin II type 1 receptor-mediated signaling pathways.

Transgenic mice constitutively overexpressing the cytokine transforming growth factor-ß1 (TGF-ß1) (TGF mice) display cerebrovascular alterations as seen in Alzheimer's disease (AD) and vascular cognitive impairment and dementia (VCID), but no or only subtle cognitive deficits. TGF-ß1 may exert part of its deleterious effects through interactions with angiotensin II (AngII) type 1 receptor (AT1R) signaling pathways. We test such interactions in the brain and cerebral vessels of TGF mice by measuring cerebrovascular reactivity, levels of protein markers of vascular fibrosis, nitric oxide synthase activity, astrogliosis, and mnemonic performance in mice treated (6 months) with the AT1R blocker losartan (10 mg/kg per day) or the angiotensin converting enzyme inhibitor enalapril (3 mg/kg per day). Both treatments restored the severely impaired cerebrovascular reactivity to acetylcholine, calcitonin gene-related peptide, endothelin-1, and the baseline availability of nitric oxide in aged TGF mice. Losartan, but not enalapril, significantly reduced astrogliosis and cerebrovascular levels of profibrotic protein connective tissue growth factor while raising levels of antifibrotic enzyme matrix metallopeptidase-9. Memory was unaffected by aging and treatments. The results suggest a pivotal role for AngII in TGF-ß1-induced cerebrovascular dysfunction and neuroinflammation through AT1R-mediated mechanisms. Further, they suggest that AngII blockers could be appropriate against vasculopathies and astrogliosis associated with AD and VCID.

Neurovascular and Cognitive failure in Alzheimer's Disease: Benefits of Cardiovascular Therapy.

Alzheimer's disease (AD) is a multifactorial and multifaceted disease for which we currently have very little to offer since there is no curative therapy, with only limited disease-modifying drugs. Recent studies in AD mouse models that recapitulate the amyloid-ß (Aß) pathology converge to demonstrate that it is possible to salvage cerebrovascular function with a variety of drugs and, particularly, therapies used to treat cardiovascular diseases such as hypercholesterolemia and hypertension. These drugs can reestablish dilatory function mediated by various endothelial and smooth muscle ion channels as well as nitric oxide availability, benefits that result in normalized brain perfusion. These cerebrovascular benefits would favor brain perfusion, which may help maintain neuronal function and, possibly, delay cognitive failure. However, restoring cerebrovascular function in AD mouse models was not necessarily accompanied by rescue of cognitive deficits related to spatial learning and memory. The results with cardiovascular therapies rather suggest that drugs originally designed to treat cardiovascular diseases that concurrently restore cerebrovascular and cognitive function do so through their pleiotropic effects. Specifically, recent findings suggest that these drugs act directly on brain cells and neuronal pathways involved in memory formation, hence, working simultaneously albeit independently on neuronal and vascular targets. These findings may help select medications for patients with cardiovascular diseases at risk of developing AD with increasing age. Further, they may identify molecular targets for recovering memory pathways that bear potential for new therapeutic avenues.

Enalapril Alone or Co-Administered with Losartan Rescues Cerebrovascular Dysfunction, but not Mnemonic Deficits or Amyloidosis in a Mouse Model of Alzheimer's Disease.

The co-administration of angiotensin converting enzyme inhibitors (ACEi) and angiotensin II (AngII) receptor blockers (ARB) that bind angiotensin type 1 receptors (AT1R) may protect from Alzheimer's disease (AD) better than each treatment taken alone. We tested the curative potential of the non brain-penetrant ACEi enalapril (3 mg/kg/day) administered for 3 months either alone or in combination with the brain penetrant ARB losartan (10 mg/kg/day) in aged (∼15 months) transgenic mice overexpressing a mutated form of the human amyloid-ß protein precursor (AßPP, thereafter APP mice). We studied cerebrovascular function, protein levels of oxidative stress markers (superoxide dismutases SOD1, SOD2 and the NADPH oxidase subunit p67phox), amyloid-ß (Aß) pathology, astrogliosis, cholinergic innervation, AT1R and angiotensin IV receptor (AT4R) levels, together with cognitive performance. Both treatments normalized cerebrovascular reactivity and p67phox protein levels, but they did not reduce the cerebrovascular levels of SOD1. Combined treatment normalized cerebrovascular SOD2 levels, significantly attenuated astrogliosis, but did not reduce the increased levels of cerebrovascular AT1R. Yet, combined therapy enhanced thioflavin-S labeled Aß plaque burden, a tendency not significant when Aß1 - 42 plaque load was considered. None of the treatments rescued cognitive deficits, cortical AT4R or cholinergic innervation. We conclude that both treatments normalized cerebrovascular function by inhibiting the AngII-induced oxidative stress cascade, and that the positive effects of the combined therapy on astrogliosis were likely due to the ability of losartan to enter brain parenchyma. However, enalapril did not potentiate, and may even dampen, the reported cognitive benefits of losartan, raising caution when selecting the most appropriate antihypertensive therapy in AD patients.

Brain kinin B1 receptor is upregulated by the oxidative stress and its activation leads to stereotypic nociceptive behavior in insulin-resistant rats.

Kinin B1 receptor (B1R) is virtually absent under physiological condition, yet it is highly expressed in models of diabetes mellitus. This study aims at determining: (1) whether B1R is induced in the brain of insulin-resistant rat through the oxidative stress; (2) the consequence of B1R activation on stereotypic nocifensive behavior; (3) the role of downstream putative mediators in B1R-induced behavioral activity. Sprague-Dawley rats were fed with 10% D-glucose in their drinking water or tap water (controls) for 4 or 12 weeks, combined either with a standard chow diet or a diet enriched with α-lipoic acid (1 g/kg feed) for 4 weeks. The distribution and density of brain B1R binding sites were assessed by autoradiography. Behavioral activity evoked by i.c.v. injection of the B1R agonist Sar-[D-Phe(8)]-des-Arg(9)-BK (10 µg) was measured before and after i.c.v. treatments with selective antagonists (10 µg) for kinin B1 (R-715, SSR240612), tachykinin NK1 (RP-67580) and glutamate NMDA (DL-AP5) receptors or with the inhibitor of NOS (L-NNA). Results showed significant increases of B1R binding sites in various brain areas of glucose-fed rats that could be prevented by the diet containing α-lipoic acid. The B1R agonist elicited head scratching, grooming, sniffing, rearing, digging, licking, face washing, wet dog shake, teeth chattering and biting in glucose-fed rats, which were absent after treatment with α-lipoic acid or antagonists/inhibitors. Data suggest that kinin B1R is upregulated by the oxidative stress in the brain of insulin-resistant rats and its activation causes stereotypic nocifensive behavior through the release of substance P, glutamate and NO.

Socio-Demographic and Behavioral Factors Associated with the Desire to Procreate Among Patients Living with HIV in Gabon.

The desire to procreate in patients living with HIV (PLHIV) has been seldom investigated in Africa, particularly in Gabon. The aim of this transversal and descriptive study was to analyze the socio-demographic and behavioral factors associated with a desire to have children in a cohort of PLHIV. The study included 442 patients, predominantly females [79.9% (337/422)], and those with a secondary school education [64.2% 271/422)]. The highest prevalence of HIV was found in patients aged 30-39 years old (44.3%), of which 59% (249/422) were unemployed. The desire to have children was noted in 78% (329/422) of patients, of which 82.4% (271/329) were treated with antiretroviral drugs; this was significantly higher in subjects under 40 years versus those over 40 years old [81% (268/329) versus 19% (61/329), p<0.001]. Sero-discordant couples represented 33.4% (110/329) of patients. The frequency of patients with the desire to have a child was significantly higher when patients wanted to hold the status of parent of a child [77% (255/329) versus 23% (74/329), p<0.001]; this was influenced by the partner's desire [60% 197/329 versus 40% (132/329), p< 0.001], as well as by the absence of weight loss [56% (185/329) versus 44% (144/329), p<0.001]. The average number of children was significantly lower in patients with the desire to procreate compared to those with no desire to have children [1.7 versus 3.2, p<0.001]. These first observations in Gabon highlight the importance of the desire to have children in PLHIV and sero-discordant couples, and they show the level of interest in developing assistance methods for procreation and family planning programs to help this population, as well as to reduce the risk of mother-to-child HIV transmission.

Angiotensin II type 1 receptor blocker losartan prevents and rescues cerebrovascular, neuropathological and cognitive deficits in an Alzheimer's disease model.

Angiotensin II (AngII) receptor blockers that bind selectively AngII type 1 (AT1) receptors may protect from Alzheimer's disease (AD). We studied the ability of the AT1 receptor antagonist losartan to cure or prevent AD hallmarks in aged (~18months at endpoint, 3months treatment) or adult (~12months at endpoint, 10months treatment) human amyloid precursor protein (APP) transgenic mice. We tested learning and memory with the Morris water maze, and evaluated neurometabolic and neurovascular coupling using [(18)F]fluoro-2-deoxy-D-glucose-PET and laser Doppler flowmetry responses to whisker stimulation. Cerebrovascular reactivity was assessed with on-line videomicroscopy. We measured protein levels of oxidative stress enzymes (superoxide dismutases SOD1, SOD2 and NADPH oxidase subunit p67phox), and quantified soluble and deposited amyloid-ß (Aß) peptide, glial fibrillary acidic protein (GFAP), AngII receptors AT1 and AT2, angiotensin IV receptor AT4, and cortical cholinergic innervation. In aged APP mice, losartan did not improve learning but it consolidated memory acquisition and recall, and rescued neurovascular and neurometabolic coupling and cerebrovascular dilatory capacity. Losartan normalized cerebrovascular p67phox and SOD2 protein levels and up-regulated those of SOD1. Losartan attenuated astrogliosis, normalized AT1 and AT4 receptor levels, but failed to rescue the cholinergic deficit and the Aß pathology. Given preventively, losartan protected cognitive function, cerebrovascular reactivity, and AT4 receptor levels. Like in aged APP mice, these benefits occurred without a decrease in soluble Aß species or plaque load. We conclude that losartan exerts potent preventive and restorative effects on AD hallmarks, possibly by mitigating AT1-initiated oxidative stress and normalizing memory-related AT4 receptors.

Cat-scratch disease in adult hospitalized for prolonged-Fever associated with multiple lymphadenopathies and weight loss.

We report a 19-year-old patient with a Cat-scratch disease presenting three months continuous alteration of the general condition, including prolonged-fever, anorexia, asthenia, weight loss associated with adenitis and multiple thoracic-abdominal adenopathies, leukocytosis with neutrophil polynuclear predominance, and increased of C-reactive protein. The serologies of toxoplasmosis, infectious mononucleosis, human immunodeficiency virus, Brucellosis, Bartonellosis and the tuberculosis research by tuberculin reaction test and Ziehl acid-alcohol resistant bacilli direct examination were negatives. The cytomegalovirus and Epstein-Barr virus serologies were positives only for immunoglobulin-G. The Bartonella henselae diagnosis was made with the analysis of histopathological specimens. The clinical and biological symptoms regressed following eight weeks of azithromycin's treatment. According to this observation, the cat-scratch disease should be considered in differential diagnosis of patients presenting prolonged-fever associated with multiple lymphadenopathies and weight loss. The azithromycin would be an alternative therapeutic issue for this pathology in case of confirmed efficacy by studies in a large patient population.

Transgenic mice overexpressing APP and transforming growth factor-beta1 feature cognitive and vascular hallmarks of Alzheimer's disease.

High brain levels of amyloid-ß (Aß) and transforming growth factor-ß1 (TGF-ß1) have been implicated in the cognitive and cerebrovascular alterations of Alzheimer's disease (AD). We sought to investigate the impact of combined increases in Aß and TGF-ß1 on cerebrovascular, neuronal, and mnemonic function using transgenic mice overproducing these peptides (A/T mice). In particular, we measured cerebrovascular reactivity, evoked cerebral blood flow and glucose uptake during brain activation, cholinergic status, and spatial memory, along with cerebrovascular fibrosis, amyloidosis, and astrogliosis, and their evolution with age. An assessment of perfusion and metabolic responses was considered timely, given ongoing efforts for their validation as AD biomarkers. Relative to wild-type littermates, A/T mice displayed an early progressive decline in cerebrovascular dilatory ability, preserved contractility, and reduction in constitutive nitric oxide synthesis that establishes resting vessel tone. Altered levels of vasodilator-synthesizing enzymes and fibrotic proteins, resistance to antioxidant treatment, and unchanged levels of the antioxidant enzyme, superoxide dismutase-2, accompanied these impairments. A/T mice featured deficient neurovascular and neurometabolic coupling to whisker stimulation, cholinergic denervation, cerebral and cerebrovascular Aß deposition, astrocyte activation, and impaired Morris water maze performance, which gained severity with age. The combined Aß- and TGF-ß1-driven pathology recapitulates salient cerebrovascular, neuronal, and cognitive AD landmarks and yields a versatile model toward highly anticipated diagnostic and therapeutic tools for patients featuring Aß and TGF-ß1 increments.

Selective in vivo antagonism of endothelin receptors in transforming growth factor-beta1 transgenic mice that mimic the vascular pathology of Alzheimer's disease.

Increased levels of transforming growth factor-beta1 (TGF-beta1) induce a vascular pathology that shares similarities with that seen in Alzheimer's disease, and which possibly contributes to the cognitive decline. In aged transgenic mice that overexpress TGF-beta1 (TGF mice), we previously found reduced dilatory function and selectively impaired endothelin-1 (ET-1)-induced contraction. Here we studied the effects of chronic treatments with selective ETA (ABT-627) or ETB (A-192621) receptor antagonist on cerebrovascular reactivity, cerebral perfusion, or memory performance. The dilatory deficit of TGF mice was not improved by either treatment, but both ET-1 contraction and basal nitric oxide (NO) production were distinctly altered. Although ABT-627 was devoid of any effect in TGF mice, it virtually abolished the ET-1-induced contraction and NO release in wild-type (WT) littermates. In contrast, A-192621 only acted upon TGF mice with full recovery of ET-1 contraction and baseline NO synthesis. TGF mice, treated or not, had no cognitive deficit in the Morris water maze, nor did ABT-627-treated WT controls despite severely impaired vasoreactivity. These findings confirm that ETA receptors primarily mediate the ET-1-induced contraction. Further, they suggest that ETB receptors play a detrimental role in conditions of increased TGF-beta1 and that vascular dysfunction does not inevitably lead to cognitive deficit.

Simvastatin improves cerebrovascular function and counters soluble amyloid-beta, inflammation and oxidative stress in aged APP mice.

Cerebrovascular dysfunctions appear to contribute to Alzheimer's disease (AD) pathogenesis and the associated cognitive decline. Recently, it has been suggested that statins could be beneficial to AD patients independently from their cholesterol-lowering effects. Using 10 month-old amyloid precursor protein transgenic mice (APP mice), we sought to reverse cerebrovascular, neuronal and memory impairments with simvastatin (20 mg/kg/day, 8 weeks). Simvastatin improved reactivity of cerebral arteries, rescued the blood flow response to neuronal activation, attenuated oxidative stress and inflammation, and reduced cortical soluble amyloid-beta (Abeta) levels and the number of Abeta plaque-related dystrophic neurites. However, at such an advanced stage of the pathology, it failed to reduce Abeta plaque load and normalize cholinergic and memory deficits. These findings demonstrate that low-dose simvastatin treatment in aged APP mice largely salvages cerebrovascular function and has benefits on several AD landmarks, which could explain some of the positive effects of statins reported in AD patients.

Complete rescue of cerebrovascular function in aged Alzheimer's disease transgenic mice by antioxidants and pioglitazone, a peroxisome proliferator-activated receptor gamma agonist.

Accumulating evidence suggests that cerebrovascular dysfunction is an important factor in the pathogenesis of Alzheimer's disease (AD). Using aged ( approximately 16 months) amyloid precursor protein (APP) transgenic mice that exhibit increased production of the amyloid-beta (Abeta) peptide and severe cerebrovascular and memory deficits, we examined the capacity of in vivo treatments with the antioxidants N-acetyl-L-cysteine (NAC) and tempol, or the peroxisome proliferator-activated receptor gamma agonist pioglitazone to rescue cerebrovascular function and selected markers of AD neuropathology. Additionally, we tested the ability of pioglitazone to normalize the impaired increases in cerebral blood flow (CBF) and glucose uptake (CGU) induced by whisker stimulation, and to reverse spatial memory deficits in the Morris water maze. All compounds fully restored cerebrovascular reactivity of isolated cerebral arteries concomitantly with changes in proteins regulating oxidative stress, without reducing brain Abeta levels or Abeta plaque load. Pioglitazone, but not NAC, significantly attenuated astroglial activation and improved, albeit nonsignificantly, the reduced cortical cholinergic innervation. Furthermore, pioglitazone completely normalized the CBF and CGU responses to increased neuronal activity, but it failed to improve spatial memory. Our results are the first to demonstrate that late pharmacological intervention with pioglitazone not only overcomes cerebrovascular dysfunction and altered neurometabolic coupling in aged APP mice, but also counteracts cerebral oxidative stress, glial activation, and, partly, cholinergic denervation. Although early or combined therapy may be warranted to improve cognition, these findings unequivocally point to pioglitazone as a most promising strategy for restoring cerebrovascular function and counteracting several AD markers detrimental to neuronal function.

Autoradiographic analysis of mouse brain kinin B1 and B2 receptors after closed head trauma and ability of Anatibant mesylate to cross the blood-brain barrier.

The potent non-peptide B2 receptor (R) antagonist, Anatibant mesylate (Ms) (LF 16-0687 Ms), reduces brain edema and improves neurological function recovery in various focal and diffuse models of traumatic brain injury in rodents. In the present study, alteration of kinin B1 and B2R after closed head trauma (CHT) and in vivo binding properties of Anatibant Ms (3 mg/kg, s.c.) injected 30 min after CHT were studied in mice by autoradiography using the radioligands [125I]HPP-Hoe 140 (B2R), and [125I]HPP-des-Arg10-Hoe 140 (B1R). Whereas B1R is barely detected in most brain regions, B2R is extensively distributed, displaying the highest densities in the hindbrain. CHT was associated with a slight increase of B1R and a decrease of B2R (10-50%) in several brain regions. Anatibant Ms (Ki = 22 pM) displaced the B2R radioligand from its binding sites in several areas of the forebrain, basal ganglia and hindbrain. Displacement was achieved in 1 h and persisted at 4 h post-injection. The inhibition did not exceed 50% of the total specific binding in non-injured mice. After CHT, the displacement by Anatibant Ms was higher and almost complete in the cortex, caudate putamen, thalamus, hippocampus, medial geniculate nucleus, ventral tegmental area, and raphe. Evans blue extravasation in brain tissue at 4 h after CHT was abolished by Anatibant Ms. It appeared that Anatibant Ms penetrated into the brain in sufficient amounts, particularly after disruption of the blood-brain barrier, to account for its B2R-mediated neuro- and vascular protective effects. The diminished binding of B2R after CHT may reflect the occupancy or internalization of B2R following the endogenous production of bradykinin (BK).

Upregulation of tachykinin NK-1 and NK-3 receptor binding sites in the spinal cord of spontaneously hypertensive rat: impact on the autonomic control of blood pressure.

1 Effects of intrathecally (i.t.) injected tachykinin NK-1 and -3 receptor agonists and antagonists were measured on mean arterial blood pressure (MAP) and heart rate (HR) in awake unrestrained spontaneously hypertensive rats (SHR,15-week-old) and age-matched Wistar Kyoto rats (WKY). Quantitative in vitro autoradiography was also performed on the lower thoracic spinal cord of both strains and Wistar rats using specific radioligands for NK-1 receptor ([(125)I]HPP[Arg(3),Sar(9),Met(O(2))(11)]SP (3-11)) and NK-3 receptor ([(125)I]HPP-Asp-Asp-Phe-N-MePhe-Gly-Leu-Met-NH(2)). 2 The NK-1 agonist [Sar(9),Met(O(2))(11)]SP (650 and 6500 pmol) decreased MAP and increased HR in WKY. The fall in MAP was blunted in SHR and substituted by increases in MAP (65-6500 pmol) and more sustained tachycardia. The NK-3 agonist senktide (6.5-65 pmol) evoked marked increases in MAP and HR (SHR>>>WKY), yet this response was rapidly desensitized. Cardiovascular effects of [Sar(9),Met(O(2))(11)]SP (650 pmol) and senktide (6.5 pmol) were selectively blocked by the prior i.t. injection of LY303870 (NK-1 antagonist, 65 nmol) and SB235375 (NK-3 antagonist, 6.5 nmol), respectively. Antagonists had no direct effect on MAP and HR in both strains. 3 Densities of NK-1 and -3 receptor binding sites were significantly increased in all laminae of the spinal cord in SHR when compared to control WKY and Wistar rats. The dissociation constant was however not affected in SHR for both NK-1 (K(d)=2.5 nM) and NK-3 (K(d)=5 nM) receptors. 4 Data highlight an upregulation of NK-1 and -3 receptor binding sites in the thoracic spinal cord of SHR that may contribute to the hypersensitivity of the pressor response to agonists and to the greater sympathetic activity seen in this model of arterial hypertension.

Hypothalamic-pituitary gonadal axis and immune response imbalance during chronic filarial infections.

Bi-directional relationships operate between the hypothalamic-pituitary-gonadal axis and the immune system. Cytokines, peptide hormones and their shared receptors/ligands are used as a common biological language for communication within and between the immune and neuroendocrine systems. Such communication suggests an immunoregulatory role for the brain and a sensory function for the immune system. We used a radioimmunoassay to measure the concentrations of steroid hormones (cortisol, testosterone, estradiol and progesterone) and pituitary hormones [follicle stimulating hormone (FSH), luteinizing hormone (LH) human chorionic gonadotropin (HCG) and prolactin] in peripheral blood plasma from 78 young Gabonese women with chronic filarial infections. We used an enzyme-linked immunosorbent assay to determine the concentrations of four proinflammatory cytokines [tumor necrosis factor-alpha (TNF-alpha), gamma interferon (IFN-gamma), interleukin-1 (IL-1) and IL-6] in the same plasma samples. Progesterone was unchanged and all other steroid hormone plasma concentrations were lower in microfilaremic women than in amicrofilaremic women. The concentration of LH was higher in amicrofilaremic women, whereas the prolactin concentration was higher in microfilaremics. The plasma concentrations of TNF-alpha, IFN-gamma, IL-1 and IL-6 were higher in microfilaremic women. A strong negative correlation was found between the steroid and pituitary hormones and the pro-inflammatory cytokines. Conversely, a strong positive correlation was found between prolactin and the same cytokines. These data provide first evidence of immune system and hormonal system disturbance during chronic filarial infections and suggest that the observed imbalance should be taken into account in the diagnosis and treatment of filarial infections.

Autoradiographic distribution and alterations of kinin B(2) receptors in the brain and spinal cord of streptozotocin-diabetic rats.

This study investigates whether bradykinin (BK) B(2) receptor binding sites are increased in the brain and thoracic spinal cord of streptozotocin (STZ)-diabetic rats at 2, 7, and 21 days posttreatment by in vitro autoradiography with the radioligand [(125)I]HPP-Hoe 140. In control and diabetic rats, specific binding sites for B(2) receptors were detected in the brain and in various laminae of the spinal cord, predominantly in superficial laminae (K(d)=34 pM). In diabetic rats, B(2) receptor densities were significantly increased in lamina l of the dorsal horn (+35% at 7 and 21 days), spinal trigeminal nucleus (+70% at 7 and 21 days) and nucleus tractus solitarius (+100% at 2 and 7 days). B(2) receptor analogues D-Arg[Hyp(3),Thi(5),D-Tic(7),Oic(8)]-BK (Hoe 140), 3-(4 hydroxyphenyl)propionyl-Hoe 140 (HPP-Hoe 140), LF16-0687 mesylate ((2-Pyrrolidinecarboxamide, N-[3-[[4-aminoiminomethyl)benzoyl]amino]propyl]-1-[[2,4-dichoro-3-[[(2,4-dimethyl-8-quinolinyl)oxy]methyl]phenyl]sulfonyl]-(2S)-(9Cl)), and BK decreased binding of [(125)I]-HPP-Hoe 140 in the spinal dorsal horn, with K(i) values of 0.5, 1.5, 3.2, and 3.7 nM, respectively. These values were not significantly different in diabetic rats at 7 days (0.5 (Hoe 140), 0.7 (HPP-Hoe 140), 1.2 (BK), and 1.7 (LF16-0687) nM). While des-Arg(10)-Hoe 140 was three orders of magnitude less potent than Hoe 140, B(1) receptor agonist (des-Arg(9)-BK) and antagonist (AcLys[D-betaNal(7),Ile(8)]des-Arg(9)-BK, R-715) did not affect [(125)I]-HPP-Hoe 140 binding at 1 microM concentration. Data suggest a very discrete and temporal increase of B(2) receptor density (without affinity changes) in the spinal cord and hindbrain of STZ-diabetic rats. This contrasts with the early induction and over-expression of B(1) receptors reported in the brain and spinal cord of STZ-diabetic rats.

Increases of spinal kinin receptor binding sites in two rat models of insulin resistance.

An autoradiographic study was conducted to determine whether kinin receptors are altered in the rat spinal cord in two experimental models of chronic hyperglycemia and insulin resistance. Sprague-Dawley rats were given 10% d-glucose in their drinking water alone or with insulin (9 mU/kg/min with osmotic pumps) for 4 weeks. Both groups and control rats were treated either with a normal chow diet or with an alpha-lipoic acid-supplemented diet as antioxidant therapy. After 4 weeks of treatment, glycemia, insulinemia, blood pressure, insulin resistance index, the production of superoxide anion in the aorta and the density of B2 receptor binding sites in the dorsal horn were significantly increased in the two models. These effects were prevented or attenuated by alpha-lipoic acid. In contrast, B2 receptor binding sites of most spinal cord laminae were increased in the glucose group only and were not affected by alpha-lipoic acid. Results show that chronic hyperglycemia associated with insulin resistance increases B1 and B2 receptor binding sites in the rat spinal cord through distinct mechanisms, including the oxidative stress for the B1 receptor.

Effects of alpha-lipoic acid on kinin B1 and B2 receptor binding sites in the spinal cord of chronically angiotensin-treated rats.

A quantitative autoradiographic study was performed to determine whether kinin receptors are altered in the rat spinal cord in an experimental model of arterial hypertension under antioxidant therapy with alpha-lipoic acid. Sprague-Dawley rats were fed for 4 weeks with a normal chow diet or with an alpha-lipoic acid supplemented diet (1000 mg/kg feed), and treated for the last 2 weeks with angiotensin II (AT II) (200 ng/kg/min with an osmotic pump implanted s.c.). Control rats received either diet but not AT II. A 2-week administration of AT II increased significantly systolic blood pressure, the production of superoxide anion in the aorta and B1 receptor binding sites in the thoracic spinal dorsal horn. This treatment did not affect spinal B2 receptor binding sites, glycemia and insulinemia. The diet supplemented with alpha-lipoic acid reduced significantly the increase in systolic blood pressure, the production of aortic superoxide anion and prevented the increases of B1 receptor binding sites. Results show an association between the oxidative stress and the increases of B1 receptors and arterial blood pressure induced by AT II. Data also exclude the possibility that arterial hypertension is a primary mechanism leading to an increase of B2 receptor binding sites in the rat spinal cord.

Expression and distribution of kinin B1 receptor in the rat brain and alterations induced by diabetes in the model of streptozotocin.

A role for kinin B1 receptors was suggested in the spinal cord and peripheral organs of streptozotocin (STZ)-diabetic rats. The present study aims at determining whether B1 receptors are also induced and over-expressed in the brain of STZ-rats at 2, 7, and 21 days post-treatment. This was addressed by in situ hybridization using the [35S]-UTPalphaS-labeled riboprobe and by in vitro autoradiography with the radioligand [125I]-HPP-des-Arg10-Hoe 140. In control rats, B1 receptor mRNA was found widely distributed in many brain regions. Low mRNA levels were found in thalamus and hypothalamus (7-12 nCi/g) while high mRNA signals were detected in cortical regions and hippocampus (18-29 nCi/g). In diabetic rats, B1 receptor mRNA was markedly increased in hippocampus, temporal/parietal cortices and amygdala at 2 and 7 days (+88 to +150%). Low densities of B1 receptor binding sites were detected in all analyzed regions in control rats (0.18-0.37 fmol/mg tissue). In diabetic rats, B1 receptor binding sites were significantly increased in hippocampus, amygdala, temporal/parietal, and perhinal/piriform cortices (+ 55 to + 165 %) at 7 days only. Results highlight an early but transient and reversible up-regulation of B1 receptors in specific brain regions of STZ-diabetic rats. This may offer the advantage of reducing putative central side effects with B1 receptor antagonists if used for the treatment of diabetic complications in the periphery.