Feeding broiler chicks diets containing keto- and hydroxy-acids: performance and carcass weight.

This study evaluated reduced dietary CP and supplementing amino acid analogs to sustain growth and carcass weight in 0- to 21-day-old Cobb × Avian-48 male broiler chicks. A total of 6 diets with 3 levels of CP (22.5, 19.5, and 16.5%) and 2 sources of AA analogs, either synthetic amino acids (SA) or keto-/hydroxy-acids (KA), were assigned randomly to 36 cages (8 chicks/cage) in a 3 × 2 factorial design. For SA diets, DL-Met, DL-Met + L-Ile, and D-Met + L-Ile + L-Val were used to supplement 22.5, 19.5, and 16.5% CP diets, respectively, and for corresponding KA diets, DL-Met was replaced with methionine hydroxy analog (MHA), L-Ile was replaced with keto-Ile, and L-Val was replaced with keto-Val. Water and all isocaloric diets (3,050 kcal ME/kg) were given ad libitum. Lowering dietary CP to 16.5% reduced BW at 7, 14, and 21 D (P ≤ 0.0001) and feed intake at 8 to 14, 15 to 21, and 0 to 21 D (P ≤ 0.001). Body weight gain (BWG) was reduced and feed-to-gain ratio (FGR) was increased (P ≤ 0.003 to 0.0001) at all times for chicks fed 16.5% CP; however, chicks fed 22.5 and 19.5% CP had comparable performance. Differences in 0 to 7 D BWG (SA, 122.9 vs. KA, 113.9 g/bird; P ≤ 0.04), a 0 to 21 D FGR cumulative effect (1.45 vs. 1.51; P ≤ 0.02), and a 15 to 21 D (P ≤ 0.04) and 0 to 21 D (P ≤ 0.05) CP × AA interaction were also observed. Greater liver weight among 16.5 vs. 19.5 or 22.5% CP fed chicks was found at 14 and 21 D (P ≤ 0.0001 and P = 0.06, respectively). Lower dietary CP reduced spleen weight on day 21 birds (P ≤ 0.0005) with lighter spleens among 16.5 and 19.5% vs. the 22.5% CP fed group (0.090, 0.095, 0.119 g/100 g BW, respectively). Breast weight at 21 D was significantly less for 16.5 vs. 22.5% CP fed chicks. Fat pad weight on day 21 was heaviest among 16.5% chicks (P ≤ 0.0004). Overall, lowering dietary CP to 16.5% had a negative effect, but keto-acid supplementation supported 0 to 21 D broiler growth compared to SA; however, transamination efficiency of KA may be lower for 0 to 7D old chicks compared to older birds.

Comparison of the protective effects of direct ischemic preconditioning and remote ischemic preconditioning in a rabbit model of transient spinal cord ischemia.

INTRODUCTION: This study aimed to determine the relative potency of direct ischemic preconditioning (DIPC) and remote ischemic preconditioning (RIPC) for protection against ischemic spinal cord injury in rabbits and to explore the mechanisms involved. METHODS: In experiment 1, we compared the neurological and histopathological outcomes of DIPC, kidney RIPC, and limb RIPC. The DIPC and kidney RIPC groups received two cycles of 5-min occlusion/15-min reperfusion of the abdominal aorta and left renal artery, respectively. The limb RIPC group received two cycles of 10-min occlusion/10-min reperfusion of the femoral arteries bilaterally. Thirty minutes after the conditioning ischemia, spinal cord ischemia was produced by occluding the abdominal aorta for 15 min. In experiments 2 and 3, we investigated whether pretreatment using a free-radical scavenger, dimethylthiourea (DMTU), an adenosine A1 receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), or a mitochondrial ATP-sensitive potassium channel antagonist, 5-hydroxydecanoate (5HD), could attenuate the protective effects of DIPC. In experiment 4, comprehensive analysis of phosphorylated proteins in the spinal cord was performed using a Proteome Profiler Array followed by immunoblotting to elucidate the signal pathway activated by DIPC. RESULTS: In experiment 1, DIPC improved the neurological and histopathological outcomes, whereas kidney and limb RIPC had no protective effects. In experiments 2 and 3, strong protective effects of DIPC were reconfirmed but were not attenuated by DMTU, DPCPX, or 5HD. In experiment 4, DIPC induced phosphorylation of Akt2. CONCLUSIONS: DIPC, but not kidney or limb RIPC, protected against ischemic spinal cord injury in rabbits. Akt2 might contribute to this protective effect.

Over-the-counter treatments for acne and rosacea.

Acne and rosacea are common inflammatory processes historically classified in the same disease category, but evolving understanding of their disparate pathophysiology and exacerbating factors have generated an enormous armamentarium of therapeutic possibilities. Patients seek over-the-counter therapies first when managing cutaneous disease; therefore, this review defines ingredients considered to be effective over-the-counter acne and rosacea products, their mechanisms, and safe formulations, including botanical components, oral supplements, and other anecdotal options in this vast skin care domain.

An evaluation of the benefits of a topical treatment in the improvement of photodamaged hands with age spots, freckles, and/or discolorations.

BACKGROUND: Photoaging of the hands is common due to frequent exposure to environmental factors. OBJECTIVE: To evaluate the efficacy of a topically applied cream formulated with an alpha-hydroxy acid, depigmenting agents, and antioxidants to improve the appearance of characteristics associated with photodamaged hands. METHODS: This was a single-site, open-label study of a proprietary topical treatment (Vivité Vibrance Décolleté, Allergan, Inc.) in adult female subjects with moderate-to-severe photoaging of the hands. The treatment was administered to the hands twice daily over an 8-week period. Treatment efficacy was assessed at baseline and weeks 4 and 8 using the Investigator Global Assessment (IGA) score based on the percentage coverage and color depth of photodamaged areas. The severity of age spots, freckles, and hand skin discoloration were also assessed; digital and ultraviolet photography of the hands was performed. Subject-reported assessments of treatment efficacy were evaluated using a questionnaire administered at week 8. Statistical significance was defined with an α set at P≤.05. RESULTS: Thirty-five subjects were enrolled with a mean age of 55.6 years; 33 subjects completed the study. The IGA of the appearance of hand photodamage improved from a mean (standard deviation) score of 5.0 (0.8) at baseline to 3.1 (1.5) and 2.6 (1.3) at weeks 4 and 8, respectively (1=mild; 9=severe). Based on expert-grader evaluation, subjects demonstrated statistically significant improvements from baseline in IGA at weeks 4 and 8 in age spots and freckling at weeks 4 and 8, (P<.0003) and in skin discolorations at week 8 (P<.05). The majority of subjects reported that they perceived improvements in each of the 9 parameters associated with skin appearance. No adverse events were reported. CONCLUSIONS: The appearance of age-related hand pigmentation characteristics were significantly improved at 4 and 8 weeks of treatment. Subjects reported post-treatment improvements in other characteristics associated with healthy skin.

A double-blind, randomized clinical trial of 20% alpha/poly hydroxy acid cream to reduce scaling of lesions associated with moderate, chronic plaque psoriasis.

BACKGROUND: Salicylic acid is a topical keratolytic agent used to reduce scaling and hyperkeratosis associated with psoriasis vulgaris. However, its use is limited due to potential systemic toxicity. Hydroxyacids also modulate keratinization and desquamation. Therefore, they may serve a beneficial role in the treatment of hyperkeratotic conditions. To date, there are no clinical studies in the literature regarding the efficacy of hydroxyacids for psoriasis treatment. PURPOSE: To evaluate the therapeutic efficacy of topical 20% alpha-hydroxy/polyhydroxy acid versus standard salicylic acid to reduce scaling in patients with moderate, chronic psoriasis. METHODS: Twenty-five subjects with moderate, chronic psoriasis were enrolled in a 2-week, double-blind, left-right, randomized, bilateral comparison clinical trial to compare the efficacy of 20% alpha-hydroxy/polyhydroxy acid emollient versus 6% salicylic acid cream and 24 were randomized/completed. Clinical evaluations to assess the severity of psoriasis and scaling were performed using a 6-point scale prior to treatment, as well as following 1 and 2 weeks of therapy. RESULTS: Twenty-four participants completed the study. Both 20% alpha-hydroxy/polyhydroxy acid emollient and 6% salicylic acid cream were efficacious in reducing scale of psoriatic lesions. The topical 20% alpha-hydroxy/polyhydroxyacid reduced scaling at a faster rate; however, following 2 weeks of treatment the efficacy of both products were relatively the same. CONCLUSION: 20% alpha-hydroxy/polyhydroxyacid is as efficacious as salicylic acid in regards to the de-scaling of psoriatic plaques. Additionally, 20% alpha-hydroxy/polyhydroxyacid cream may yield quicker results and less toxicity than salicylic acid.

Efficacy and safety of a new superficial chemical peel using alpha-hydroxy acid, vitamin C and oxygen for melasma.

BACKGROUND: Facial skin pigmentary disorders can be resistant to conventional treatment. Superficial chemical peel is an effective and safe treatment in pigmentary problems including melasma, post-inflammatory hyperpigmentation and aging spots. OBJECTIVE: To assess the efficacy and safety of new superficial chemical peel (Melasma peel, Theraderm®), this is composed of alpha-hydroxy acid (AHAs), vitamin C and oxygen for melasma. METHODS: Twenty-five ethnic Korean patients (Fitzpatrick skin phototypes IV and V) with moderate to severe melasma were enrolled. The patients underwent four treatments at 1-2-week intervals for 8 weeks. Clinical improvement was evaluated on a 5-point scale by participants and by the same dermatologist, and adverse effects were checked during the study. RESULTS: Improvement in the degree of pigmentation, pores, and evenness were noted. Significant clinical improvement of hyperpigmentation was evident. No adverse effects were reported. CONCLUSION: New superficial chemical peel using AHAs, vitamin C and oxygen is an effective and very safe treatment for melasma.

[Features phase transfer catalytic glycosylation of aromatic hydroxy acids].

The catalytic phase transfer reactions of per acetylated alpha-D-glucosaminyl chloride with isomeric hydroxybenzoic, 1-hydroxy-2-naphthoic acids in solid potassium carbonate--acetonitrile were studied. It was found that the composition and yields of reaction products are determined by the nature of the source ofcarboxylic acids, lipophilic phase transfer catalyst, temperature. For the first time found that the O-beta-glycosyl esters of ortho-hydroxyaromatic acids in the presence of potassium carbonate can anomerizovatsya in 1,2-cis derivatives. The structure of the synthesized compounds proved 1H NMR spectroscopy. In in vivo experiments it was established that glycosyl esters of salicylic acid and per acetylated 2-carboxy phenylglucosaminide exhibit analgesic activity similar to aspirin.

Oral adjuvant activity for nasal influenza vaccines caused by combination of two trihydroxy fatty acid stereoisomers from the tuber of Pinellia ternata.

Pinellic acid from the tuber of Pinellia ternata was isolated as an effective oral adjuvant for nasal influenza vaccine, and identified 9S,12S,13S-trihydroxy-10E-octadecenoic acid (9S,12S,13S) by the enantioselective total synthesis [Nagai et al., Int. Immunopharmacol., 2, 1183-93 (2002); Shirahata et al., Tetrahedron, 62, 9483-96 (2006)]. However, present study showed that synthetic 9S,12S,13S that was nearly 100% pure was not effective as an oral adjuvant. HPLC analysis also showed that the adjuvant active pinellic acid fraction from tuber of P. ternata contained the 9S,12S,13S as the main component and at least two minor components. Therefore seven other chemically synthesized stereoisomers were tested in combination with the 9S,12S,13S for oral adjuvant activity. Only the 9S,12S,13S in combination with the 9S,12R,13R isomer in a weight% ratio of 90.4:9.6 (pinellic acid mixture, PAM) was a potent oral adjuvant and elicited both antiviral IgA antibody (Ab) in bronchoalveolar lavage fluids and nasal washes and antiviral IgG(1) Ab in mice sera. Oral administration of the PAM followed by nasal influenza vaccination and infection with A/PR/8/34 virus showed increases in survival rate (22%, control versus 78% test) in mice orally administered PAM as adjuvant. Histopathological examination of lung tissue of mice given oral PAM with vaccine followed by influenza virus infection showed attenuated infiltration of inflammatory cells with decreases in the alveolar spaces and increases in the alveolar septa. The result of this study refutes the our previous study and suggests that the combination of 9S,12S,13S and 9S,12R,13R isomers is necessary for effective oral adjuvant activity when used in conjunction with nasal influenza vaccine.

Local therapy as basic anti-aging prevention.

Skin, the largest organ of the body, is the organ in which changes associated with aging are most visible. Intrinsic (chronologic) skin aging is characterized by atrophy of the skin with loss of elasticity and slowed metabolic activity. With superposition of environmental damage, particularly exposure to ultraviolet radiation (photodamage) on the intrinsic aging, the process results, at least initially, in hypertrophic repair response with thickened epidermis and increased melanogenesis. Even more striking changes occur in the dermis, i.e., massive elastosis (deposition of abnormal elastic fibers), collagen degeneration, and twisted, dilated microvasculature. Regular use of a sunscreen alone appears to allow for some repair as well as protection from further photodamage. Local anti-aging therapy has been shown to partially reverse the clinical and histologic changes induced by the combination of sunlight exposure and chronologic aging. Histologic changes in the epidermis and dermis noted after 12 months suggest repair of photodamage by reconstitution of rete pegs, repair of keratinocyte ultrastructural damage, more even distribution of melanocytes and melanin pigment, deposition of new papillary dermal collagen, and improvements in vasculature. Hyperkeratinization is normalized, while epidermal thickness and dermal glycosaminoglycan content are increased. Briefly, many of the unwanted changes can be improved by topical therapy.

Intracisternal administration of glibenclamide or 5-hydroxydecanoate does not reverse the neuroprotective effect of ketogenic diet against ischemic brain injury-induced neurodegeneration.

PRIMARY OBJECTIVE: To investigate the role of ATP-sensitive potassium (K(ATP)) channels in the neuroprotective effects of a ketogenic diet against cardiac arrest-induced cerebral ischemic brain injury-induced neurodegeneration. RESEARCH DESIGN: Male Sprague Dawley rats were randomly divided into three groups and were fed with a ketogenic diet for 25 days before being subjected to a cardiac arrest-induced cerebral ischemia for 8 minutes 30 seconds. Four hours before cardiac arrest-induced cerebral ischemia, one group was intracisternally injected with glibenclamide, a plasma membrane K(ATP) channel blocker. The second group was injected with 5-hydroxydecanoate, a mitochondrial K(ATP) channel blocker. The third group was without the pre-treatment with K(ATP) channel antagonist. Nine days after the cardiac arrest, rats were sacrificed. Fluoro-jade (FJ) staining was used to evaluate cerebral ischemic neurodegeneration in the rat brain sections. MAIN OUTCOMES AND RESULTS: The number of FJ-positive degenerating neurons in the CA1 area of the hippocampus, the cerebellum and the thalamic reticular nucleus of the ketogenic diet-fed rats with or without glibenclamide or 5-hydroxydecanoate pre-treatment before cardiac arrest-induced cerebral ischemia is zero. CONCLUSIONS: The results suggest that K(ATP) channels do not play a significant role in the neuroprotective effects of the ketogenic diet against cardiac arrest-induced cerebral ischemic injury-induced neurodegeneration.

The role of cosmeceuticals in antiaging therapy.

As baby boomers get older, they have shown an increasing interest in maintaining a youthful appearance. As a result, there has been a corresponding increase in topical antiaging formulations, which are commonly referred to as cosmeceuticals. These products come with a seemingly limitless number of key active ingredients and claims of reducing the signs of aging and/or maintaining a youthful appearance. This paper reviews the more common cosmeceutical ingredients.

Clinical tolerance and efficacy of capryloyl salicylic acid peel compared to a glycolic acid peel in subjects with fine lines/wrinkles and hyperpigmented skin.

BACKGROUND: Several chemical agents are currently used to perform superficial peels of the face to reduce facial hyperpigmentation and fine lines/wrinkles. Some of the most commonly used agents are alpha hydroxyl acids, such as glycolic acid (GA), or beta hydroxy acid, such as salicylic acid. AIM: This study aims to compare the efficacy of GA to that of a novel derivative of salicylic acid, capryloyl salicylic acid (LHA). SUBJECTS/METHODS: In a split-face study, 50 female volunteers between the ages of 35 and 60 years with mild to moderate facial hyperpigmentation and fine lines/wrinkles were randomized and LHA or GA peel was applied to one side of the face. Increasing peel concentrations were applied (5-10% LHA or 20-50% GA) based on the tolerance level of the subjects and clinical observations of an expert dermatologist for 12 weeks at biweekly intervals. RESULTS: Of the 44 volunteers who completed the study, at 12 weeks 41% of LHA-treated and 30% of GA-treated subjects demonstrated significant reduction of fine lines/wrinkles compared to baseline. Forty-six percent of LHA-treated subjects and 34% of GA-treated subjects showed significant reduction of hyperpigmentation compared to baseline. LHA treatment was better than GA peels, although there were no statistically significant differences between the two groups. CONCLUSIONS: Five percent to 10% of LHA peel is generally safe and as effective as 20-50% GA peel in reducing facial hyperpigmentation and fine lines/wrinkles.

Comparison of alpha- and beta-hydroxy acid chemical peels in the treatment of mild to moderately severe facial acne vulgaris.

BACKGROUND: Chemical peels are used as adjuvants for treatment of facial acne. No well-controlled studies have compared alpha- and beta-hydroxy acid peels in the treatment of mild to moderately severe facial acne. OBJECTIVE: To compare the efficacy of alpha- and beta-hydroxy acid chemical peels in the treatment of mild to moderately severe facial acne vulgaris. MATERIALS AND METHODS: Twenty patients were recruited in this split-face, double-blind, randomized, controlled study. An alpha-hydroxy acid (30% glycolic acid) was applied to one-half of the face and a beta-hydroxy acid peel (30% salicylic acid) was applied contralaterally every 2 weeks for a total of six treatments. A blinded evaluator performed quantitative assessment of papules and pustules. RESULTS: Both chemical peels were significantly effective by the second treatment (p<.05) and there were no significant differences in effectiveness between the two peels. At 2 months posttreatment, the salicylic acid peel had sustained effectiveness. More adverse events were reported with the glycolic acid peel after the initial treatment. CONCLUSION: The glycolic acid and salicylic acid peels were similarly effective. The salicylic acid peel had sustained effectiveness and fewer side effects. Alpha- and beta-hydroxy acid peels both offer successful adjunctive treatment of facial acne vulgaris.

Systemic administration of diazoxide induces delayed preconditioning against transient focal cerebral ischemia in rats.

Diazoxide is the prototypical opener of mitochondrial ATP-sensitive potassium channels (mitoK(ATP)) and protects neurons in vivo and in vitro against chemical and anoxic stresses. While we have previously shown that diazoxide administration induces acute preconditioning against transient cerebral ischemia in rats, the potential for delayed preconditioning of diazoxide has not been examined. The purpose of this study was to determine whether diazoxide promotes delayed preconditioning following 90 min of middle cerebral artery occlusion (MCAO) in male Wistar rats. Diazoxide (10 mg/kg) or vehicle was injected intraperitoneally 24 h before MCAO. Infarct volumes were measured 72 h after reperfusion. In animals anesthetized with halothane, treatment with diazoxide exhibited a 35% reduction (48.3+/-3.0% to 31.3+/-4.8%) and 18% reduction (35.1+/-2.2% to 28.9+/-2.1%) in cortical and subcortical infarct volumes, respectively. Administration of the mitoK(ATP) blocker 5-hydroxydecanoate attenuated this beneficial effect. In contrast, diazoxide did not induce delayed preconditioning in isoflurane-anesthetized rats. These findings support the concept that diazoxide produces delayed preconditioning via mitoK(ATP) activation but that physiological status can affect induction of preconditioning.

Managing acne vulgaris effectively.

The management of acne is a gratifying experience. Available treatments are effective, relatively nontoxic and generally safe. However, there is no quick fix. Antibiotics, hormone therapies and topical therapies are maintenance treatments. Isotretinoin can induce remission, as can some of the newer physical modalities of lights, lasers and radiofrequency devices. Effective management of acne often requires using a combination of treatments that act on different parts of the pathogenic process of acne development.

Inhibition of cardiac contractility by 5-hydroxydecanoate and tetraphenylphosphonium ion: a possible role of mitoKATP in response to inotropic stress.

This study investigates the role of the mitochondrial ATP-sensitive K+ channel (mitoKATP) in response to positive inotropic stress. In Langendorff-perfused rat hearts, inotropy was induced by increasing perfusate calcium to 4 mM, by adding 80 microM ouabain or 0.25 microM dobutamine. Each of these treatments resulted in a sustained increase in rate-pressure product (RPP) of approximately 60%. Inhibition of mitoKATP by perfusion of 5-hydroxydecanoate (5-HD) or tetraphenylphosphonium before induction of inotropic stress resulted in a marked attenuation of RPP. Inhibition of mitoKATP after induction of stress caused the inability of the heart to maintain a high-work state. In human atrial fibers, the increase in contractility induced by dobutamine was inhibited 60% by 5-HD. In permeabilized fibers from the Langendorff-perfused rat hearts, inhibition of mitoKATP resulted, in all cases, in an alteration of adenine nucleotide compartmentation, as reflected by a 60% decrease in the half-saturation constant for ADP [K1/2 (ADP)]. We conclude that opening of cardiac mitoKATP is essential for an appropriate response to positive inotropic stress and propose that its involvement proceeds through the prevention of stress-induced decrease in mitochondrial matrix volume. These results indicate a physiological role for mitoKATP in inotropy and, by extension, in heart failure.

Effects of alpha-hydroxy acids on the human skin of Japanese subjects: the rationale for chemical peeling.

Alpha-hydroxy acid (AHA) agents, such as glycolic acid and lactic acid, have been used as therapeutic agents for more than a quarter of a century. Recently, they have been used as agents to rejuvenate photo-aged skin. It is believed that these AHA agents induce the epidermis to remodel and accelerate desquamation, thus exerting their therapeutic effects. In this study, we investigated the histological differences in skin treated with glycolic, lactic, citric and acetic acids once daily for 6 weeks. The melanin pigments in the basal layer were less prominent in the glycolic and lactic acid-treated skin than in the citric and acetic acid-treated skin. The melanin deposits in the horny layers were equal for all AHA. However, the melanin deposits in the squamous layers were less prominent in the glycolic and lactic acid-treated skins than in the citric and acetic acid-treated skins; this was analogous to observations of the basal layers. Collagen I and procollagen I were increased after treatment with glycolic, lactic and citric acid in the upper dermis, but were not increased with acetic acid treatment. However, the staining of the epidermis and dermis for matrix metalloproteinase-1 (MMP-1) after treatment was not significantly different among the agents. Our data suggest that longer treatment intervals with glycolic and lactic acid can cause improvements in both the epidermal and dermal components and support the usefulness of AHA for rejuvenating photo-damaged skin.

Activation of mitochondrial ATP-sensitive potassium channels improves rotenone-related motor and neurochemical alterations in rats.

Our previous studies revealed that activation of mitochondrial ATP-sensitive potassium channels exerted protective effects on rotenone-treated rats and cultured cells. The aim of the present study is to examine the potential therapeutic effects of iptakalim, an ATP-sensitive potassium-channel opener, and diazoxide, a selective mitochondrial ATP-sensitive potassium-channel opener, on Parkinsonian symptoms in rats induced by rotenone. Rats were treated with rotenone (2.5 mg/kg s.c.) daily for 4 wk. This treatment caused a depletion of dopamine in the striatum and substantia nigra. Behaviourally, rotenone-infused rats exhibit Parkinsonian symptoms. Catalepsy was estimated by a 9-cm bar test. Treatment with L-dopa (10 mg/kg.d p.o.), iptakalim (0.75, 1.5, 3.0 mg/kg.d p.o.) and diazoxide (3.0 mg/kg.d p.o.) for 2 wk improved behavioural dysfunction and elevated dopamine contents in the striatum and substantia nigra of rotenone-treated rats. Studies also found that iptakalim and diazoxide could reduce the enzymic activities and mRNA levels of inducible nitric oxide synthase elicited by chronic administration of rotenone. All neurorestorative effects by both iptakalim and diazoxide were abolished by 5-hydroxydecanoate, a selective mitochondrial ATP-sensitive potassium-channel blocker. Collectively, the data suggested that mitochondrial ATP-sensitive potassium channels play a key role in improving both Parkinsonian symptoms and neurochemistry alterations of rotenone model rats, and selective activation of mitochondrial ATP-sensitive potassium channels may provide a new therapeutic strategy for treatment of early Parkinson's disease.

A role of opening of mitochondrial ATP-sensitive potassium channels in the infarct size-limiting effect of ischemic preconditioning via activation of protein kinase C in the canine heart.

The opening of mitochondrial ATP-sensitive K+ (mitoK(ATP)) channels triggers or mediates the infarct size (IS)-limiting effect of ischemic preconditioning (IP). Because ecto-5'-nucleotidase related to IP is activated by PKC, we tested whether the opening of mitoK(ATP) channels activates PKC and contributes to either activation of ecto-5'-nucleotidase or IS-limiting effect. In dogs, IP procedure decreased IS and activated ecto-5'-nucleotidase, both of which were mimicked by transient exposure to either cromakalim or diazoxide, and these effects were blunted by either GF109203X (a PKC inhibitor) or 5-hydroxydecanoate (a mitoK(ATP) channel blocker), but not by HMR-1098 (a surface sarcolenmal K(ATP) channel blocker). Either cromakalim or diazoxide activated both PKC and ecto-5'-nucleotidase, which was blunted by either GF109203X or 5-hydroxydecanoate, but not by HMR-1098. We concluded that the opening of mitoK(ATP) channels contributes to either activation of ecto-5'-nucleotidase or the infarct size-limiting effect via activation of PKC in canine hearts.

Intrahippocampal administration of the branched-chain alpha-hydroxy acids accumulating in maple syrup urine disease compromises rat performance in aversive and non-aversive behavioral tasks.

Maple syrup urine disease (MSUD) is an inherited metabolic disease predominantly characterized by neurological dysfunction. Although a variable degree of psychomotor/delay/mental retardation is found in a considerable number of MSUD patients, the mechanisms underlying the neuropathology of this disorder are yet not defined. The present study investigated the effect of acute intrahippocampal administration of the branched-chain alpha-hydroxy acids (BCHA) accumulating in MSUD on rat behavior in non-aversive (open field) and aversive (inhibitory avoidance) tasks. Cannulated 60-day-old male Wistar rats received bilateral intrahippocampal injection of alpha-hydroxyisocaproic acid (HIC, 1.5 micromol), alpha-hydroxyisovaleric acid (HIV, 2.5 micromol), alpha-hydroxy-beta-methyl-n-valeric acid (HMV, 1.5 micromol), or NaCl (2.5 micromol)(controls) immediately after or 10 min before training. Testing session was performed 24 h later. Administration of the hydroxy acids immediately after training caused no effect on the cognitive performance of the rats. In contrast, HIV and HMV administered 10 min before training provoked a habituation deficit in the open field task. Motor activity, assessed by crossing responses, was the same for the groups infused with BCHA and NaCl. The effect of MK-801, succinate, creatine, and the antioxidants ascorbic acid plus alpha-tocopherol on the behavioral alterations provoked by HIV in the open field task revealed that only the energetic substrates (succinate and creatine) prevented these effects, reflecting a possible compromise of brain energy production by HIV. We also observed that rats pretreated with HIC, HIV, or HMV did not increase their latency in the testing session in the step-down inhibitory avoidance task, revealing an impairment of retrieval (memory retention or acquisition) in this task. Furthermore, no differences between controls and rats receiving BCHA were detected in the latency to leave the platform in the training test, suggesting similar motor activity of all groups. The data indicate that the alpha-hydroxy acids accumulating in MSUD impair cognition and may be implicated in the neuropathology and psychomotor delay/mental retardation observed in the affected patients.