A quick test to objectify smell and taste dysfunction at home: a proof of concept for the validation of the chemosensory perception test.

Recent studies have shown the efficacy of a home test for the self-evaluation of olfactory and gustatory functions in quarantined coronavirus disease-2019 (COVID-19) patients. However, testing was often limited to COVID-19 participants, and the accuracy of home test kits was rarely compared to standardized testing. This study aims at providing proof of concept for the validation of the new Chemosensory Perception Test (CPT) developed to remotely assess orthonasal olfactory, retronasal olfactory, and gustatory functions in various populations using common North American household items. In the 2 experiments, a total of 121 participants irrespective of having olfactory and/or gustatory complaints from various causes (COVID-19, sinunasal, post-viral, idiopathic) were tested first, with one or many of the following tests: (i) a brief chemosensory questionnaire, (ii) an olfactory test-Sniffin' Sticks Test (SST) or University of Pennsylvania Smell Identification Test (UPSIT), and/or (iii) a gustatory test-Brief Waterless Empirical Taste Test (B-WETT). We then applied the CPT which yielded 3 different subscores, namely orthonasal, retronasal, and gustatory CPT scores. The orthonasal CPT score was significantly correlated with SST (ρ = 0.837, P < 0.001) and UPSIT (ρ = 0.364, P < 0.001) scores, and exhibited an excellent accuracy to identify olfactory dysfunction (OD) as compared to SST (area under the curve [AUC]: 0.923 [95% confidence interval {CI}, 0.822-1.000], P < 0.001). The retronasal CPT score but not the gustatory CPT score allowed to distinguish between participants with or without subjective gustatory complaint (AUC: 0.818 [95% CI, 0.726-0.909], P < 0.001). The CPT has the ability to identify OD and to quantify subjective gustatory complaints.

Olfactory Training Impacts Olfactory Dysfunction Induced by COVID-19: A Pilot Study.

INTRODUCTION: Olfactory dysfunction is one of the main symptoms of COVID-19 and may last beyond resolution of the infection. The most promising intervention for post-viral olfactory dysfunction is olfactory training (OT), which involves exposing the olfactory system to a range of odors daily. This approach is thought of promoting the regeneration of olfactory receptor cells, but its effectiveness in patients with post-COVID-19 olfactory dysfunction has yet to be confirmed. METHODS: This double-blind randomized pilot study compared the effectiveness of OT versus placebo in the treatment of post-COVID-19 olfactory dysfunction. Twenty-five participants were recruited in each group. OT protocol consisted of sniffing 4 scents (rose, orange, clove, and eucalyptus) for 5 min twice daily for 12 weeks. Olfactory function was assessed before and after the training using (1) a validated odor identification test (UPSIT-40) and (2) a 10-point visual analog scale; we further assessed the presence of (3) parosmia. RESULTS: While we did not observe any effect of OT on olfactory test scores, we observed a significant improvement of subjective olfactory function in the intervention group, while no such effect was observed in the placebo group. Finally, the frequency of parosmia was significantly lower in the intervention group. CONCLUSIONS: This study highlights an increase in subjective but not objective olfactory function when performing OT for 12 weeks. Further, parosmia seems to be positively affected by OT. These results may serve as a starting point for larger scale studies to assess the efficacy of OT for treatment of post-COVID-19 olfactory dysfunction.

Occupational health profile of Canadian Maritimes truck drivers.

BACKGROUND: There are over 12,000 professional truck drivers in the Canadian Maritime provinces, with the majority being in New Brunswick and Nova Scotia. Previous studies have focused on the health of Canadian and American truck drivers but the occupational health status of truck drivers in the Maritime Provinces remains undocumented. OBJECTIVE: The objective of this cross-sectional study was to provide a general, occupational health and demographic characteristics description of professional truck drivers in the Maritimes. METHODS: One-hundred and four male truck drivers from the Canadian Maritime Provinces volunteered for this study. Nine occupational health indicators were measured (seven were self-reported via questionnaire and two were physical measurements). Participants self-reported their age, years of truck driving experience and education. RESULTS: Only one-quarter of the current sample had no health conditions. In contrast, more than half were obese, one third had back problems, and one-sixth had a high risk of developing cardiovascular disease (CVD). The group comparison analysis showed that the group without health condition was younger and more educated than the group with multiple health conditions. For this study, age and low rate of education were associated with an increased number of health conditions. CONCLUSIONS: Similar to health profiles of other populations of North American truck drivers, this study suggests that the majority of truck drivers in the Canadian Maritime Provinces have at least one poor indicator of occupational health.

The intake of an extract from seeds of Tamarindus indica L. modulates the endocrine function of adult male mice under a high fat diet.

TBP is a natural product from Tamarindus indica L. seeds used as a natural remedy in India. This product is an antioxidant and may have beneficial effects on endocrine and metabolic functions. However, the regulatory mechanisms involved remain to be elucidated. In males, testosterone is synthesized by Leydig cells from the testis. With aging and obesity, testis function declines, leading to decreased testosterone synthesis. The aim of the current research is to determine how TBP improves testosterone production in male mice under a high fat diet leading to hypoandrogenic condition. Using C2C12 myoblast cells, we have found that TBP increased mitochondrial mass and oxygen respiration, as well as the production of the IGF-1 hormone. In addition, treatment of TM3 Leydig cells with TBP resulted in increased testosterone production. In mice under a high fat diet, TBP lowered blood glucose level and corticosterone production and improved total testosterone production after five weeks of treatment. In addition, testicular expressions of genes encoding the mitochondrial transporter of cholesterol (Star) and steroidogenic enzymes (Cyp11a1, Hsd3b1, Cyp17a1 and Hsd17b3) were increased by TBP. Hence, TBP may prevent the detrimental effects of long-term consumption of a high fat diet and may have health benefits on the endocrine function.

Shear wave elastography potential to characterize spastic muscles in stroke survivors: Literature review.

BACKGROUND: Post-stroke spasticity contributes to impairments, disabilities and decline in quality of life. Quantitative measurements of spasticity are needed in order to assess the impact of specific treatments and to choose the more accurate technique for each patient. The aim of this review is to examine the use of shear wave ultrasound elastography as a quantitative tool for monitoring biomechanical muscle properties such as stiffness and to determine whether it is a reliable method to assess spastic muscle in stroke survivors. METHODS: Studies were sought from Academic Search Complete, CINAHL, PubMed/Medline, Scopus and SportDiscus with the following keywords: shear wave elastography, spasticity, stiffness, elasticity, hardness, stroke, cerebrovascular accident, cerebral vascular event and transient ischaemic attack. Titles and abstracts were screened, and relevant full-text articles were retrieved for further review. FINDINGS: Of the 76 screened studies, nine captured elastography data of the spastic biceps brachii (n = 6) or the plantar flexors (n = 3) with stroke victims. All consulted studies had a different way of utilizing this technology which was expected considering no guidelines had been developed. Shear wave speed values obtained are compared and discussed with clinical measures. Reliability of the devices is also discussed. INTERPRETATION: Shear wave ultrasound elastography can provide useful quantitative information on the mechanical properties of the spastic muscles in post-stroke patients. Nevertheless, new studies using common terminology and parameters are needed to develop reliable methods that could help in assessing treatment efficiency.

Avoidance of the vaginal incision site for mesh placement in vaginal wall prolapse surgery: A prospective study.

OBJECTIVE: To evaluate efficacy of a minimal surface area, vaginally-installed polypropylene tape (VPT), avoiding insertion on the incision line to treat an anterior, posterior or anteroposterior vaginal wall prolapse. STUDY DESIGN: Patients with an anterior, posterior or anteroposterior vaginal wall prolapse waiting for surgical treatment were included in the study. Primary outcome was the incidence of prolapse recurrence reported with combined outcome measures and was reported with Kaplan-Meier cumulative incidence. Secondary outcomes were operative complications, adverse events, urinary, colorectal and sexual functions as well as quality of life. Participation in the study involved up to 8 visits over 5 years. At each visit, patients used a self-reported questionnaire to report symptoms related to pain, urinary, colorectal, sexual functions, and quality of life. A physical examination was also performed. Paired t-tests were used to investigate change in POP-Q and quality of life measurements since baseline. RESULTS: 71 patients underwent the procedure and were followed-up for an average (standard deviation) of 32.5 (18.7) months. Only 2 (2.8%) women experienced a recurrence of their pelvic organ prolapse. Only one case of erosion and no case of persistent pain have been recorded up to 5 years post-surgery. Quality of life was improved and then sustained throughout the follow-up period (p<0.01). CONCLUSION: This VPT surgical procedure is safe and has a high level of efficacy to treat anterior, posterior or anteroposterior vaginal wall prolapse. It is also associated with improvements in quality of life of patients which are sustained for many years.

Olfactory ensheathing cells but not fibroblasts reduce the duration of autonomic dysreflexia in spinal cord injured rats.

Autonomic dysreflexia is a common complication after high level spinal cord injury and can be life-threatening. We have previously shown that the acute transplantation of olfactory ensheathing cells into the lesion site of rats transected at the fourth thoracic spinal cord level reduced autonomic dysreflexia up to 8weeks after spinal cord injury. This beneficial effect was correlated with changes in the morphology of sympathetic preganglionic neurons despite the olfactory cells surviving no longer than 3weeks. Thus the transitory presence of olfactory ensheathing cells at the injury site initiated long-term functional as well as morphological changes in the sympathetic preganglionic neurons. The primary aim of the present study was to evaluate whether olfactory ensheathing cells survive after transplantation within the parenchyma close to sympathetic preganglionic neurons and whether, in this position, they still reduce the duration of autonomic dysreflexia and modulate sympathetic preganglionic neuron morphology. The second aim was to quantify the density of synapses on the somata of sympathetic preganglionic neurons with the hypothesis that the reduction of autonomic dysreflexia requires synaptic changes. As a third aim, we evaluated the cell type-specificity of olfactory ensheathing cells by comparing their effects with a control group transplanted with fibroblasts. Animals transplanted with OECs had a faster recovery from hypertension induced by colorectal distension at 6 and 7weeks but not at 8weeks after T4 spinal cord transection. Olfactory ensheathing cells survived for at least 8weeks and were observed adjacent to sympathetic preganglionic neurons whose overall number of primary dendrites was reduced and the synaptic density on the somata increased, both caudal to the lesion site. Our results showed a long term cell type-specific effects of olfactory ensheathing cells on sympathetic preganglionic neurons morphology and on the synaptic density on their somata, and a transient cell type-specific reduction of autonomic dysreflexia.

MicroRNAs as potential circulating biomarkers for amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a condition primarily characterized by the selective loss of upper and lower motor neurons. Motor neuron loss gives rise to muscle tissue malfunctions, including weakness, spasticity, atrophy, and ultimately paralysis, with death typically due to respiratory failure within 2 to 5 years of symptoms' onset. The mean delay in time from presentation to diagnosis remains at over 1 year. Biomarkers are urgently needed to facilitate ALS diagnosis and prognosis as well as to act as indicators of therapeutic response in clinical trials. MicroRNAs (miRNAs) are small molecules that can influence posttranscriptional gene expression of a variety of transcript targets. Interestingly, miRNAs can be released into the circulation by pathologically affected tissues. This review presents therapeutic and diagnostic challenges associated with ALS, highlights the potential role of miRNAs in ALS, and discusses the diagnostic potential of these molecules in identifying ALS-specific miRNAs or in distinguishing between the various genotypic and phenotypic forms of ALS.

Specific targeting of the IL-23 receptor, using a novel small peptide noncompetitive antagonist, decreases the inflammatory response.

IL-23 is part of the IL-12 family of cytokines and is composed of the p19 subunit specific to IL-23 and the p40 subunit shared with IL-12. IL-23 specifically contributes to the inflammatory process of multiple chronic inflammatory autoimmune disorders, including psoriasis, multiple sclerosis, inflammatory bowel disease, and rheumatoid arthritis. So far, one antibody targeting the shared p40 subunit of IL-12 and IL-23, Ustekinumab, is approved clinically to treat psoriasis. However, there are no treatments inhibiting specifically the IL-23 proinflammatory response. We have developed small IL-23R-specific antagonists by designing all D-peptides arising from flexible regions of IL-23R. Of these peptides, we selected 2305 (teeeqqly), since in addition to its soluble properties, it inhibited IL-23-induced STAT3 phosphorylation in spleen cells. Peptide 2305 specifically binds to IL-23R/IL-12Rß1-expressing HEK-293 cells and not to cells devoid of the receptor. Peptide 2305 showed functional selectivity by modulating IL-23-induced gene expression in IL-23R/IL-12Rß1-expressing cells and in Jurkat cells; 2305 does not inhibit IL-12-induced cytokine expression in IL-12Rß-IL-12Rß2-HEK-293 cells. Finally, compared with anti-p40 treatment, 2305 effectively and selectively inhibits IL-23-induced inflammation in three in vivo mouse models: IL-23-induced ear inflammation, anti-CD40-induced systemic inflammatory response, and collagen-induced arthritis. We, hereby, describe the discovery and characterization of a potent IL-23R small-peptide modulator, 2305 (teeeqqly), that is effective in vivo. 2305 may be more convenient, less cumbersome, less costly, and most importantly, more specific than current biologics for the treatment of inflammatory conditions, and conceivably complement the actual therapies for these chronic and debilitating inflammatory diseases.

Immunological demyelination triggers macrophage/microglial cells activation without inducing astrogliosis.

The glial scar formed by reactive astrocytes and axon growth inhibitors associated with myelin play important roles in the failure of axonal regeneration following central nervous system (CNS) injury. Our laboratory has previously demonstrated that immunological demyelination of the CNS facilitates regeneration of severed axons following spinal cord injury. In the present study, we evaluate whether immunological demyelination is accompanied with astrogliosis. We compared the astrogliosis and macrophage/microglial cell responses 7 days after either immunological demyelination or a stab injury to the dorsal funiculus. Both lesions induced a strong activated macrophage/microglial cells response which was significantly higher within regions of immunological demyelination. However, immunological demyelination regions were not accompanied by astrogliosis compared to stab injury that induced astrogliosis which extended several millimeters above and below the lesions, evidenced by astroglial hypertrophy, formation of a glial scar, and upregulation of intermediate filaments glial fibrillary acidic protein (GFAP). Moreover, a stab or a hemisection lesion directly within immunological demyelination regions did not induced astrogliosis within the immunological demyelination region. These results suggest that immunological demyelination creates a unique environment in which astrocytes do not form a glial scar and provides a unique model to understand the putative interaction between astrocytes and activated macrophage/microglial cells.

Implications of leptin in neuroendocrine regulation of male reproduction.

Obesity is a major health problem contributing to increased subfertility in males, as well as increased morbidity for diseases related to a decline in testosterone production with aging. Leptin is a hormone produced by adipose tissue whose production increases with the amount of body fat. Several studies have supported a relationship between increased leptin production and regulation of reproductive function. Indeed, leptin acts at all levels of the hypothalamus-pituitary-gonadal (HPG) axis in males. However, most of the obese individuals become insensitive to increased endogenous leptin production and develop a functional leptin resistance. This deregulation of leptin signaling might result in abnormal endocrine and reproductive functions. Altered leptin dynamics may contribute to male infertility in different ways, leading to hypogonadism. These include leptin resistance or leptin insufficiency at the hypothalamus and leptin modulation of testicular physiology. In this review, we address the mechanisms of action of leptin at different levels of the HPG axis. Moreover, the influences of leptin on steroidogenesis and spermatogenesis, as well as seasonal variations of leptin's action on male reproduction are discussed.

Antiangiogenic activity of aganirsen in nonhuman primate and rodent models of retinal neovascular disease after topical administration.

PURPOSE: Aganirsen, an antisense oligonucleotide inhibiting insulin receptor substrate (IRS)-1 expression, has been shown to promote the regression of pathologic corneal neovascularization in patients. In this study, the authors aimed to demonstrate the antiangiogenic activity of aganirsen in animal models of retinal neovascularization. METHODS: Eyedrops of aganirsen were applied daily in nonhuman primates after laser-induced choroidal neovascularization (CNV; model of wet age-related macular degeneration [AMD]) and in newborn rats after oxygen-induced retinopathy (OIR; model of ischemic retinopathy). Retinal aganirsen concentrations were assessed in rabbits and monkeys after topical delivery (21.5, 43, or 86 µg). Clinical significance was further evaluated by determination of IRS-1 expression in monkey and human retinal biopsy specimens. RESULTS: Topical corneal application of aganirsen attenuated neovascular lesion development dose dependently in African green monkeys. The incidence of high-grade CNV lesions (grade IV) decreased from 20.5% in vehicle-treated animals to 1.7% (P < 0.05) at the 86-µg dose. Topical aganirsen inhibited retinal neovascularization after OIR in rats (P < 0.05); furthermore, a single intravitreal injection of aganirsen reduced OIR as effectively as ranibizumab, and their effects were additive. Significantly, topical applications of aganirsen did not interfere with physiological retinal vessel development in newborn rats. Retinal delivery after topical administration was confirmed, and retinal expression of IRS-1 was demonstrated to be elevated in patients with subretinal neovascularization and AMD. CONCLUSIONS: Topical application of aganirsen offers a safe and effective therapy for both choroidal and retinal neovascularization without preventing its normal vascularization. Together, these findings support the clinical testing of aganirsen for human retinal neovascular diseases.

Compensatory mechanisms to maintain blood pressure in paraplegic rats: implication of central tachykinin NK-1 and NK-3 receptors?

People with high level spinal cord injury (SCI) suffer from both hypotension and spontaneous hypertension due to loss of supraspinal control of spinal sympathetic outflow. Few reports have addressed whether any changes occur in central regulation of blood pressure (BP) and heart rat (HR) at the supraspinal level. Central tachykinin NK-1 and NK-3 receptors are located in many cardiovascular areas in the brain and are known to modulate BP and HR. This study examined the intracerebroventricular (i.c.v.) effects of the selective NK-1 receptor agonist [Sar(9), Met(O(2))(11)]SP (65pmol, n=6) and NK-3 receptor agonist senktide (650pmol, n=6) on mean arterial pressure (MAP) and HR before and after complete spinal cord transection at thoracic level 4 (T4). [Sar(9), Met(O(2))(11)]SP evoked increases in MAP and HR which were still present 4days after the T4 SCI. Further analysis using the beta(1)-adrenoceptor antagonist atenolol (10mgkg(-1)) revealed an increased contribution of HR in the MAP increase after SCI. For senktide, 2 and 5weeks after T4 SCI, the rise in MAP induced by senktide was significantly increased in magnitude and was similar to a normal response at 8weeks. These effects were accompanied by a bradycardia, which was still present and amplified at 8weeks. Our results reveal a transient potentiation of the senktide-mediated MAP effect and a greater contribution of the HR in MAP increase by [Sar(9), Met(O(2))(11)]SP in T4 transected rats. Although the significance of these changes remains to be established. This suggest a reorganization of supraspinal mechanisms regulating BP and HR after a high level SCI. Central NK-1 and NK-3 receptors might therefore contribute to the maintenance of MAP following high thoracic SCI.

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.

Transplantation of human embryonic stem cell-derived oligodendrocyte progenitors into rat spinal cord injuries does not cause harm.

Demyelination contributes to loss of function following spinal cord injury. We have shown previously that transplantation of human embryonic stem cell-derived oligodendrocyte progenitors into adult rat 200 kD contusive spinal cord injury sites enhances remyelination and promotes recovery of motor function. Previous studies using oligodendrocyte lineage cells have noted a correlation between the presence of demyelinating pathology and the survival and migration rate of the transplanted cells. The present study compared the survival and migration of human embryonic stem cell-derived oligodendrocyte progenitors injected 7 days after a 200 or 50 kD contusive spinal cord injury, as well as the locomotor outcome of transplantation. Our findings indicate that a 200 kD spinal cord injury induces extensive demyelination, whereas a 50 kD spinal cord injury induces no detectable demyelination. Cells transplanted into the 200 kD injury group survived, migrated, and resulted in robust remyelination, replicating our previous studies. In contrast, cells transplanted into the 50 kD injury group survived, exhibited limited migration, and failed to induce remyelination as demyelination in this injury group was absent. Animals that received a 50 kD injury displayed only a transient decline in locomotor function as a result of the injury. Importantly, human embryonic stem cell-derived oligodendrocyte progenitor transplants into the 50 kD injury group did not cause a further decline in locomotion. Our studies highlight the importance of a demyelinating pathology as a prerequisite for the function of transplanted myelinogenic cells. In addition, our results indicate that transplantation of human embryonic stem cell-derived oligodendrocyte progenitor cells into the injured spinal cord is not associated with a decline in locomotor function.

A noninvasive ultrasonographic method to evaluate bladder function recovery in spinal cord injured rats.

Suprasacral spinal cord injury induces changes in the mechanical and neuronal properties of the bladder resulting in bladder areflexia followed by bladder-sphincter dyssynergia and detrusor muscle hypertrophy, which lead to urinary retention and increased bladder size. These changes are most often quantified using highly skilled urodynamic techniques that involve catheterization. We investigated whether a hand-held digital ultrasound imaging system could monitor urinary retention in the bladder following spinal cord injury in adult rats. Our findings indicate that contusive spinal cord injury resulted in high residual bladder volumes that decreased and stabilized by 2 weeks post-injury but remained significantly higher than control bladder volumes up to 46 days post-injury (the longest time point examined). Post hoc analysis indicated that the degree of bladder function recovery recorded at the end of the study correlated with the degree of bladder function recovery recorded at 6 days post-injury, indicating that bladder function recovery can be predicted by analyzing bladder volume as early as 6 days post-injury. Bladder function recovery correlated with locomotor recovery as assessed using the BBB locomotor rating scale. While providing a noninvasive assessment of bladder function with no detrimental impact on locomotor function or assessment, this protocol provides researchers with a clinically relevant outcome measure for quantifying bladder function recovery after spinal cord injury or after experimental treatments for spinal cord injury.

Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury.

Demyelination contributes to loss of function after spinal cord injury, and thus a potential therapeutic strategy involves replacing myelin-forming cells. Here, we show that transplantation of human embryonic stem cell (hESC)-derived oligodendrocyte progenitor cells (OPCs) into adult rat spinal cord injuries enhances remyelination and promotes improvement of motor function. OPCs were injected 7 d or 10 months after injury. In both cases, transplanted cells survived, redistributed over short distances, and differentiated into oligodendrocytes. Animals that received OPCs 7 d after injury exhibited enhanced remyelination and substantially improved locomotor ability. In contrast, when OPCs were transplanted 10 months after injury, there was no enhanced remyelination or locomotor recovery. These studies document the feasibility of predifferentiating hESCs into functional OPCs and demonstrate their therapeutic potential at early time points after spinal cord injury.

Expression of kinin B1 receptors in the spinal cord of streptozotocin-diabetic rat.

Previous studies have reported cardiovascular and nociceptive responses after intrathecal injection of kinin B1 receptor (B1R) agonists in the model of streptozotocin (STZ)-diabetic rat (diabetic). The aim of this study was to measure the early up-regulation of B1R binding sites and mRNA in the thoracic spinal cord of diabetic and control rats. Data show significant increases of specific B1R binding sites in the dorsal horn of diabetic rats 2 days (+315%), 7 days (+303%) and 21 days (+181%) after STZ treatment. Levels of mRNA were significantly increased (+68%) at 2 and 7 days but not at 21 days. These data bring the first molecular evidence for an early up-regulation of B1R in the spinal cord of diabetic rat.

Correlation between brain bradykinin receptor binding sites and cardiovascular function in young and adult spontaneously hypertensive rats.

Intracerebroventricular (i.c.v.) effects of bradykinin (BK) B(1) and B(2) receptor agonists and antagonists were assessed on mean arterial blood pressure (MAP) and heart rate (HR) in awake unrestrained spontaneously hypertensive rats (SHR, aged of 8 and 16 weeks) and age-matched Wistar Kyoto rats (WKY). Quantitative in vitro autoradiographic studies were also performed on the brain of both strains with specific radioligands for B(2) receptors [(125)I]HPP-Hoe 140 and B(1) receptors [(125)I]HPP-des-Arg(10) and Hoe140. MAP increased linearly with doses of BK (81-8100 pmol) and the amplitudes were significantly greater in SHR, particularly at 16 weeks. While BK evoked a negative linear trend on HR (bradycardia) in WKY, a positive one (tachycardia) was observed in adult SHR. In both strains, BK-induced pressor response was blocked by equimolar doses of B(2) receptor antagonist, D-Arg-[Hyp(3), Thi(5), D-Tic(7), Oic(8)]-BK (Hoe 140), but not by B(1) receptor antagonist, AcLys[D-betaNal(7), Ile(8)]des-Arg(9)-BK (R-715). B(1) receptor agonists (Sar-[D-Phe(8)]-des-Arg(9)-BK, des-Arg(9)-BK, des-Arg(10)-Kallidin) and antagonist (R-715 alone or with Hoe 140) had no or marginal effect on MAP and HR at doses up to 8100 pmol in SHR and WKY. Higher densities of specific [(125)I]HPP-Hoe 140 labelling were found in discrete brain areas of SHR, especially in regions associated with cardiovascular function. Low levels of [(125)I]HPP-[des-Arg(10)]-Hoe140 binding sites were seen in WKY and SHR, yet densities were significantly greater in midbrain and cortical regions of SHR aged of 16 weeks. Contrary to SHR, ageing caused a downregulation of B(2) and B(1) receptor binding sites in specific brain nuclei in WKY. It is concluded that the hypersensitivity of the pressor response to i.c.v. BK in SHR occurs during both the early and established phases of hypertension in parallel with the enhancement of B(2) receptor binding sites in various cardiovascular brain centres. In contrast, brain B(1) receptors do not seem to participate in the central pressor effects of kinins nor in the maintenance of hypertension in SHR.

Chronic effects of angiotensin-converting enzyme inhibition on kinin receptor binding sites in the rat spinal cord.

With the use of in vitro receptor autoradiography, this study aims at determining whether the higher level of kinin B(2) receptor density in the spinal cord of the spontaneously hypertensive rat (SHR) is secondary to arterial hypertension and whether chronic treatment with angiotensin I-converting enzyme inhibitors (ACEI) can regulate neuronal B(1) and B(2) receptors. SHR received, from the age of 4 wk, one of the two ACEI (lisinopril or zofenopril, 10 mg x kg(-1) x day(-1)) or for comparison, the selective AT(1) antagonist (losartan, 20 mg x kg(-1) x day(-1)) in their drinking water for a period of 4, 12, and 20 wk. Age-matched untreated SHR and Wistar-Kyoto rats (WKY) were used as controls. B(2) receptor binding sites in most laminae were higher in SHR than in WKY from the age of 8 to 24 wk. Whereas B(1) receptor binding sites were significantly present in young SHR and WKY, they were barely detectable in adult rats. ACEI (16 and 24 wk) and AT(1) antagonist (24 wk) enhanced the number of B(2) without changing B(1) receptor binding sites. However, at 8 wk the three treatments significantly increased B(1) and decreased B(2) receptors in lamina I. It is concluded that 1) the higher density of B(2) receptors in the spinal cord of SHR is not due to hypertension, 2) kinin receptors are regulated differently by ACEI in neuronal and vascular tissues, and 3) aging may have a profound impact on levels of B(1) and B(2) receptors in the rat spinal cord.