Potential mechanisms of neuroprotection induced by low dose total-body γ-irradiation in C57 mice administered with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

Low dose total-body γ-irradiation (TBI) was reported to confer neuroprotection against MPTP-induced dopaminergic neurotoxicity. After being pretreated with a single low dose (0.5 Gy, 2.0 Gy or 3.5 Gy) TBI, C57BL/6 mice were administered with MPTP (15 mg/kg, four times, 2 h apart) intraperitoneally (i.p.). In the group pretreated with 2.0 Gy TBI, with lower lymphocytes number, neuroprotection was found by High Performance Liquid Chromatography (HPLC) determination of the striatal dopamine. Contrarily, in the group pretreated with 0.5 Gy TBI, with higher lymphocytes number, dopaminergic neuron toxicity was enhanced. So it was probably the decrease of lymphocytes, not the radiation hormesis that rendered the potential neuroprotection. And it was the balance between radiation injury and lymphocytopenia neuroprotection that decided the effect of low dose γ-irradiation on MPTP-induced dopaminergic neurotoxicity.     

The stimulatory effects of caffeine with oseltamivir (Tamiflu) on light–dark behavior and open-field behavior in mice

Abnormal behaviors and death associated with the use of oseltamivir (Tamiflu^®) have emerged as a major issue in influenza patients taking the drug. Here, we investigated the mechanisms underlying the effects of oseltamivir on the behavior of mice using light–dark and open-field preference tests. Oseltamivir (75 and 150 mg/kg, intraperitoneally (i.p.)) alone affected neither time spent in the open area in the light–dark preference test nor ambulation in the open-field test at 2 h post-injection. However, a non-selective adenosine A₁/A₂ receptor antagonist, caffeine (10 mg/kg, i.p.) in combination with oseltamivir (150 mg/kg, i.p.) increased time spent in the open area in the light–dark preference test. This enhancement was not inhibited by a benzodiazepine receptor antagonist, flumazenil (10–20 mg/kg, subcutaneously (s.c.)). Enhancement of ambulation in the open-field test was also observed when caffeine (10 mg/kg, i.p.) was combined with oseltamivir (150 mg/kg, i.p.). This enhancement was inhibited by a dopamine D₂ receptor antagonist, haloperidol (0.1 mg/kg, s.c.). Furthermore, an adenosine A₂ receptor antagonist, SCH58261 (3 mg/kg, i.p.) in combination with oseltamivir (150 mg/kg, i.p.) increased ambulation in the open-field test, while an adenosine A₁ receptor antagonist, DPCPX (1–3 mg/kg, i.p.) did not. These findings suggest that the actions of oseltamivir may involve the dopamine and adenosine systems. Our findings suggest that due to the interaction between central blockade of adenosine A₂ receptors by caffeine, and oseltamivir-induced behavioral changes, patients being treated with oseltamivir should be closely monitored.     

Lipoic acid effects on lipid peroxidation level,superoxide dismutase activity and monoamines concentration in rat hippocampus

The purposes of the present work were to verify lipid peroxidation level, superoxide dismutase (SOD) activity and monoamines (dopamine (DA), norepinephrine (NE), serotonin (5-HT)), and their metabolites (3,4-hydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA)) contents in rat hippocampus after lipoic acid (LA) administration. Wistar rats were treated with 0.9% saline (i.p., control group) and LA (10, 20 or 30 mg/kg, i.p., LA10, LA20 and LA30 groups, respectively). After the treatments all groups were observed for 24 h. In LA20 group only there was a significant decrease in lipid peroxidation level. However, no alteration was observed in SOD activity in groups treated with LA. The NE and DA levels were increased only in 20 mg/kg dose of LA in rat hippocampus. Serotonin content and their metabolite 5-HIAA levels was decreased in same dose of LA. On the other hand, DOPAC and HVA levels did not show any significant change. The reduction in lipid peroxidation level and alterations in hippocampal monoamines can be suggested as a possible brain mechanism from this antioxidant. The outcome of the study may have therapeutic implications in the neurodegenerative diseases.     

Real-time voltammetric detection of cocaine-induced dopamine changes in the striatum of freely moving mice

In the present voltammetric study, we have characterized cocaine-induced changes in evoked dopamine release and uptake in the striatum of freely moving mice in real time. Cocaine induced marked dopamine uptake inhibition measured as apparent K_m changes, producing a maximal effect 20 min following a single injection (15 mg/kg, i.p.). Changes in uptake were paralleled by increases in evoked dopamine release per stimulus pulse, revealing a high correlation between these two parameters following cocaine administration. This initial characterization of cocaine effects on striatal dopamine transmission in the commonly used C57BL/6 mouse strain provides a basis for future voltammetric studies using genetic mouse models.     

Altered extracellular levels of DOPAC and HVA in the rat nucleus accumbens shell in response to sub-chronic nandrolone administration and a subsequent amphetamine challenge

Associated with acts of violence and polydrug use, abuse of anabolic androgenic steroids (AAS) is an increasing problem in society. The aim of the present study was to elucidate whether sub-chronic treatment with the AAS nandrolone decanoate affects dopamine release and dopamine metabolism in the rat nucleus accumbens shell, before and after an amphetamine challenge. Male Sprague–Dawley rats received daily i.m. injections of nandrolone decanoate (15 mg/kg) or vehicle for 14 days. On day 15, the animals were anaesthetized and a microdialysis probe was implanted into the nucleus accumbens shell. Extracellular fluid was collected 1 h before and 3 h after a single amphetamine injection (5 mg/kg). The samples were then analyzed regarding the content of dopamine, and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), using HPLC with electrochemical detection. Two weeks of nandrolone decanoate administration caused a significant decrease of the basal DOPAC and HVA levels, which remained low during the first hour following the amphetamine challenge. Dopamine levels did not differ significantly between groups, neither after the nandrolone pre-treatment nor the amphetamine challenge. In conclusion, these novel findings indicate that AAS alter the metabolism of dopamine in a brain region involved in the development of drug dependence.     

Oleic acid modulation of the immune response in wound healing: A new approach for skin repair

Injury triggers inflammatory responses and tissue repair. Several treatments are currently in use to accelerate healing; however, more efficient formulations are still needed for specific injuries. Since unsaturated fatty acids modulate immune responses, we aimed to evaluate their therapeutic effects on wound healing. Skin wounds were induced in BALB/c mice and treated for 5 days with n-3, n-9 fatty acids or vehicle (control). n-9 treated mice presented smaller wounds than control and n-3 at 120 h post-surgery (p.s.). Collagen III mRNA, TIMP1 and MMP9 were significantly elevated in n-9 group compared to n-3 or vehicle at 120 h p.s. Among the inflammatory mediators studied we found that IL-10, TNF-α and IL-17 were also higher in n-9 treated group compared to n-3 or vehicle at 120 h p.s. Interestingly, COX2 had decreased expression on wound tissue treated with n-9. Inflammatory infiltrate analysis revealed diminished frequency of CD4⁺, CD8⁺ and CD11b⁺ cells in n-9 wounds at 24 and 120 h p.s., which was not related to cell death, since in vitro apoptosis experiments did not show any cell damage after fatty acids administration. These results suggested that unsaturated fatty acids, specifically n-9, modulate the inflammation in the wound and enhance reparative response in vivo. n-9 may be a useful tool in the treatment of cutaneous wounds.     

Effects of berberine on 6-hydroxydopamine-induced neurotoxicity in PC12 cells and a rat model of Parkinson's disease

Protoberberine isoquinoline alkaloids including berberine inhibit dopamine biosynthesis and aggravate l-DOPA-induced cytotoxicity in PC12 cells. In this study, the effects of berberine on 6-hydroxydopamine (6-OHDA)-induced cytotoxicity in PC12 cells and on unilateral 6-OHDA-lesioned rats were investigated. In PC12 cells, berberine at 10 and 30 μM associated with 6-OHDA (10, 20, and 50 μM) enhanced cytotoxicity at 48 h compared to 6-OHDA alone, indicated by an increase in apoptotic cell death. In addition, treatment with berberine (5 and 30 mg/kg, i.p.) for 21 days in 6-OHDA-lesioned rats markedly depleted tyrosine hydroxylase-immunopositive cells in the substantia nigra as compared to berberine-untreated rats. Further, the levels of dopamine and norepinephrine were also significantly decreased by berberine administration (5 and 30 mg/kg) in the striatal regions of 6-OHDA-lesioned rats. These results suggested that berberine aggravated 6-OHDA-induced cytotoxicity in PC12 cells, and led to the degeneration of dopaminergic neuronal cells in the substantia nigra of 6-OHDA-lesioned rats. It is, therefore, suggested that the use of long-term l-DOPA therapy with isoquinoline derivatives including berberine may need to be examined for the presence of adverse symptoms.     

De novo arachidonic acid synthesis in Perkinsus marinus, a protozoan parasite of the eastern oyster Crassostrea virginica

The capability of synthesizing fatty acids de novo in the meront stage of the oyster protozoan parasite, Perkinsus marinus, was investigated employing stable-isotope-labeled precursors (1,2 13C-acetate and palmitic-d(31) acid). Fatty acid methyl esters derived from 1,2 13C-acetate and palmitic-d(31) acid were analyzed using gas chromatography/mass spectrometry and gas chromatography/flame ionization detection. Results revealed that in vitro cultured P. marinus meronts utilized 13C-acetate to synthesize a range of saturated and unsaturated fatty acids. The saturated fatty acids 14:0, 16:0, 18:0, 20:0, 22:0, 24:0 and the unsaturated fatty acids, 18:1(n-9), 18:2(n-6), 20:1(n-9), 20:2(n-6), 20:2(n-9), 20:3(n-6), 20:4(n-6) were found to contain 13C, after 7, 14, and 21 days incubation with the precursor. This indicates that meronts can synthesize fatty acid de novo using acetate as a substrate. Meronts efficiently elongated 16:0-d(31) to 18:0, 20:0, 22:0, 24:0, but desaturation activity was limited, after 7 and 14 days cultivation. Only a small quantity of 18:1-d(29) was detected. This suggests that meronts cannot directly convert exogenous palmitic acid or its products of elongation to unsaturated counterparts. The ability to synthesize 20:4(n-6) from acetate is particularly interesting. No parasitic protozoan has been reported to be capable of synthesizing long chain essential fatty acids, such as 20:4(n-6) de novo. Future study will be directed to determine whether the observed in vitro activities indeed reflect the in vivo activities, when meronts are associated with the host.     

Poly(ADP-ribose) polymerase-1 is involved in the neuronal death induced by quinolinic acid in rats

Reactive oxygen and nitrogen species formation leads to DNA damage in animals treated with quinolinic acid. Poly(ADP-ribose) polymerase-1 (PARP-1) is a protein involved in the DNA base excision repair system. Its overactivation promotes cellular energy deficit and necrosis. Here, we evaluated the effect of PJ-34, a potent inhibitor of PARP-1, on the neuronal damage induced by quinolinic acid. Animals were administered with PJ-34 (10 mg/kg, i.p.), 1 h before and 1 h after a striatal infusion of 1 μl of quinolinic acid (240 nmol). PJ-34 clearly attenuated the circling behavior produced by quinolinic acid and completely prevented the histological damage induced by the toxin. The protective effect of PJ-34 suggests that PARP-1 activation is playing an active role in the neuronal death induced by quinolinic acid.     

Assessing palatability of long-chain fatty acids from the licking behavior of BALB/c mice

Dietary oils such as corn oil, olive oil, and canola oil, which primarily contain triacylglycerol and small quantities of fatty acids, are highly palatable to animals. In a previous study, we examined the short-term (60 s) licking behavior of mice and observed that they exhibited a high licking response to a low concentration of fatty acid (linoleic acid), which is comparable to that observed for pure corn oil. This finding suggests that fatty acids contribute to the palatability of dietary oils. In order to supplement our knowledge of the fundamental features of fatty acid palatability in the oral cavity, we assessed the licking behavior of BALB/c mice to investigate the palatability of various types of long-chain fatty acids. The mice showed high licking responses to 1% unsaturated 16- and 18-carbon fatty acids (palmitoleic acid, 16:1; oleic acid, 18:1; linoleic acid, 18:2; and linolenic acid, 18:3), low licking responses to 16- and 20-carbon fatty acids (palmitic acid, 16:0 and arachidonic acid, 20:4), and no significant response to saturated fatty acids (stearic acid, 18:0 and arachidic acid, 20:0) or fatty acid derivatives (methyl linoleate and linole alcohol). Additionally, there were differences in the palatability of 18-carbon unsaturated fatty acids at very low concentrations. At fatty acid concentrations of 0.04% and 0.0625%, the mice showed significant preference for linoleic acid and linolenic acid, but not oleic acid, when compared with mineral oil. These results suggest that mice show high licking responses to 16- and 18-carbon unsaturated long-chain fatty acids at low concentrations. Further, we suggest that sensitivity to fatty acids is affected by the saturated state of the fatty acid, carbon chain length, and terminal carboxyl group.     

Effects of oleic acid, docosahexaenoic acid and eicosapentaenoic acid on background and genotoxin-induced frequencies of SCEs in Indian muntjac fibroblasts.

Muntjac cells were cultured at 5 X 10(5) cells/10 cm Petri dish for 24 h prior to addition of fatty acids (50 microM) which were delivered to the cells complexed with 2% bovine serum albumin (fatty acid-free) and incubated for a further 24 h. Parallel dishes were processed for lipid extraction and GC analysis. This analysis showed highly significant (P < 0.01) uptake by the cells of each fatty acid. Genotoxins (75 microM hydrogen peroxide, 20 microM t-butylhydroperoxide and 2.4 microM mitomycin C) were added to the cells for 1 h prior to the end of the 24 h fatty acid incubation period. Control (no genotoxin or fatty acid) treatments were included. No difference was observed in background frequencies of SCEs between controls and fatty acid treatments, thus indicating that these fatty acids per se do not cause DNA damage. The cells incubated with the genotoxins showed increased (P < 0.05) frequencies of SCEs when compared with control frequencies. Cells incubated with genotoxins in the presence of fatty acids also showed significantly higher (P < 0.05) levels of SCEs when compared with control frequencies. When cells supplemented with genotoxins in the presence of fatty acids were compared with cells treated with genotoxins alone, higher levels of SCEs were observed in the former, suggesting that the fatty acids exacerbate DNA damage caused by these genotoxins.     

Cisplatin-induced long-term dynorphin A-immunoreactivity in cell somata of rat area postrema neurons

We evaluated long-term dynorphin A-immunoreactivity in the rat area postrema (AP) after the administration of cisplatin. First, rats were given 1, 5 and 10 mg/kg body weight cisplatin (i.p.) and their behavior was monitored for 72 h. We observed a delayed increase in pica 24-72 h after injection, compared to the 24 h before injection. We attributed this to the cisplatin injection. Pica was defined as an increase in the intake of non-nutritional matter such as kaolin. Administration of 1, 5 and 10 mg/kg cisplatin led to an increase in kaolin intake on day 1. Administration of 5 and 10 mg/kg of cisplatin led to decreased intake of laboratory chow (MF) on days 1–3, but 10 mg/kg cisplatin causes an excessive aggravation of their condition. Following this behavioral experiment, we immunohistochemically examined the induction of dynorphin A in the AP at 24, 48 and 72 h post-administration of 1 and 5 mg/kg cisplatin. Administration of 5 mg/kg cisplatin caused dynorphin A to accumulate gradually in the neurosoma of the AP neurons, and the numbers of positive AP neurosomata at 48 and 72 h post-administration were higher than following an equal dosage of 0.9% NaCl. These findings suggest that dynorphin A increases in the central nervous system for a long time following administration, and causes certain behavioral and clinical changes, including those related to appetite and nausea.     

Neuroprotection by caffeine: time course and role of its metabolites in the MPTP model of Parkinson's disease

Epidemiological studies have raised the possibility of caffeine serving as a neuroprotective agent in Parkinson's disease (PD). This possibility has gained support from findings that dopaminergic neuron toxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or other neurotoxins is attenuated by co-administration of caffeine in mice. Here we examined the time window of caffeine's neuroprotection as well as the effects of caffeine's metabolites (theophylline and paraxanthine) in the MPTP mouse model of PD. In the first experiment, caffeine pre-treatment (30 mg/kg ip) significantly attenuated MPTP-induced striatal dopamine depletion when it was given 10 min, 30 min, 1 h, or 2 h but not 6 h before MPTP (40 mg/kg ip) treatment. Meanwhile, caffeine post-treatment also significantly attenuated striatal dopamine loss when it was given 10 min, 30 min, 1 h or 2 h but not 4 h, 8 h or 24 h after MPTP injection. In the second experiment, both theophylline (10 or 20 mg/kg) and paraxanthine (10 or 30 mg/kg) administration (10 min before MPTP) significantly attenuated MPTP-induced dopamine depletion in mice, as did caffeine (10 mg/kg) treatment. Thus the metabolites of caffeine also provide neuroprotective effects in this mouse model of PD. The data suggest that if caffeine protects against putative toxin-induced dopaminergic neuron injury in humans, then precise temporal pairing between caffeine and toxin exposures may not be critical because the duration of neuroprotection by caffeine may be extended by protective effects of its major metabolites.     

The study of ISO induced heart failure rat model

Objective

To find a more excellent large-dose isoproterenol (ISO) induced heart failure (HF) rat model.

Methods

166 male Wistar rats were divided into four groups, normal group (n = 10), 85/85 mg/kg group (n = 50), 85/340 mg/kg group (n = 50) and 340/340 mg/kg group (n = 56). HF was induced by two subcutaneous injections of homologous ISO on 2 consecutive days. We calculated death rate of each ISO group on different time points. And all the survival ISO rats were examined by echocardiography separately on 2 weeks, 3 weeks and 4 weeks. We defined the EF < 45% rats as heart failure, and calculated EF < 45% rate of three ISO groups. 4 weeks after the last injection, all of the rats were sacrificed. H&E and Masson staining were used to evaluate inflammatory infiltration and myocardial fibrosis, and immunohistochemistry was used to measure the levels of IL-1, IL-6 and IL-17. We also treated adult rat cardiac fibroblasts with IL-1, IL-6, IL-17, or PBS for 24 h, and real-time PCR was used to measure the expressions of MMP-2 and MMP-9 in treated fibroblasts.

Results

Through 4-week observation, we found that the period within 2 days after the last injection was the most dangerous one for all the ISO rats, regardless of injection dose. Then, the death rate increased slowly. 4 weeks later, the death rates were respectively 30% in 85/85 mg/kg group, 60% in 85/340 mg/kg group, and 68% in 340/340 mg/kg group, and there were statistical differences among three experimental groups. Moreover, the EF < 45% rate and cardiac fibrosis rate were 100% in 85/340 mg/kg group as same as 340/340 mg/kg group, and much higher than 85/85 mg/kg group. Furthermore, we also found that pro-inflammatory cytokines (IL-1, IL-6 and IL-17) increased in 85/340 mg/kg group compared with normal group, and above cytokines could induce MMP-2 and MMP-9 expression in cardiac fibroblasts.

Conclusion

85/340 mg/kg ISO induced HF rat model was superior to the other two dose ISO induced HF rat models. Pro-inflammatory cytokines might contribute to HF and myocardial fibrosis through promotion of MMPs expression in cardiac fibroblasts.     

Inhibitory Action of Fatty Acids on the Growth of Neisseria gonorrhoeae

Fatty acids of various chain lengths (C(1) to C(24)) were examined for their effects on growth, oxygen consumption, and in vitro reduced nicotinamide adenine dinucleotide oxidase activity of Neisseria gonorrhoeae CS-7. The growth inhibition caused by saturated fatty acids increased with increasing chain length to a maximum with palmitic acid (C(16)). Stearic acid (C(18)) and longer saturated fatty acids showed little inhibition of growth. However, unsaturated fatty acids of chain length C(16) to C(20) were inhibitory. Similar inhibition was observed with Bacillus subtilis and a deep rough mutant of Salmonella typhimurium. Wildtype S. typhimurium and Pseudomonas aeruginosa were more resistant to medium-chain (C(7) to C(10)) fatty acids and completely resistant to long-chain (C(12) to C(18)) fatty acids. Thus, sensitivity of N. gonorrhoeae to long-chain fatty acids appears to be related to the permeability of the outer membrane. Growth inhibition by short-chain (C(1) to C(6)) fatty acids was pH dependent; inhibition of growth increased with decreasing pH. Saturated fatty acids inhibited oxygen consumption by log-phase cells of N. gonorrhoeae. This inhibition increased with increasing chain length to a maximum observed with myristic acid (C(14)). Whereas stearic acid (C(18)) had little effect upon oxygen consumption, unsaturated C(18) fatty acids were inhibitory. An in vitro inhibition of reduced nicotinamide adenine dinucleotide oxidase activity by saturated (C(1) to C(12)) and unsaturated (C(16) to C(20)) fatty acids was also observed. Although the inhibitory concentrations were generally higher than those required to inhibit growth or oxygen consumption, an inhibition of electron transport may be partially responsible for the observed growth inhibition.     

Low serum fatty acid levels in pregnancies with fetal gastroschisis: A prospective study

Fetal gastroschisis is a paraumbilical abdominal wall defect with herniation of abdominal organs. The underlying cause of the disease remains unknown; however, studies suggest that nutritional factors may play a role in its development. This prospective case‐control study explored the association of serum fatty acid levels of pregnant women and occurrence of gastroschisis. Gastroschisis group comprised 57 pregnant women with fetuses with gastroschisis, and the control group comprised 114 pregnant women with normal fetuses. Serum fatty acids levels were compared between the groups for the overall pregnancy at <34 weeks; ≤25 weeks, and >25 and <34 weeks; and at delivery. Total fatty acids (p = .008), unsaturated fatty acids (p = .002), and the C18:1n9/C18:00 ratio (p = .021) were lower in the gastroschisis group than in the control group during the overall pregnancy; however, the C16:00/C18:2n6 ratio (p = .018) was higher in the gastroschisis group than in the control group during the same period. Total fatty acids (p = .044) and unsaturated fatty acids (p = .024) were lower in the gastroschisis group at ≤25 weeks, and unsaturated fatty acid (p = .025) and the C18:1n9/C18:00 ratio (p = .013) were lower in the gastroschisis group than in the control group at >25 and <34 weeks. Pregnant women with fetuses with gastroschisis have low serum fatty acids levels during pregnancy. These findings suggest that fatty acids levels may be involved in the pathogenesis of fetal gastroschisis.     

The cannabinoid antagonist SR 141716A (Rimonabant) reduces the increase of extra-cellular dopamine release in the rat nucleus accumbens induced by a novel high palatable food

The assumption of a novel high palatable food (a candied cherry) occurs concomitantly with an increase in the concentration of extra-cellular dopamine and its main metabolite 3,4-dihydroxy-phenylacetic acid (DOPAC) by about 45% in the dialysate obtained by intracerebral microdialysis from the shell of the nucleus accumbens of male rats. Such increase was reversed by SR 141716A (Rimonabant), a selective cannabinoid CB1 receptor antagonist (0.3 mg/kg i.p. and 1 mg/kg i.p.), which also reduces the assumption of the high palatable food, when given 15 min before exposure to the candied cherry. SR 141716A effects on extracellular dopamine and DOPAC were prevented by WIN 55,212-2 (0.3 mg/kg i.p.) or HU 210 (0.1 mg/kg i.p.) given 15 min before SR 141716A. The present results show for the first time that SR 141716A reduces the increase in extra-cellular dopamine induced by a novel high palatable food in the nucleus accumbens. This confirms that cannabinoid CB1 receptors play a key role in food intake and/or appetite and suggests that the mesolimbic dopaminergic system is involved at least in part, in the effects of cannabinoid receptor agonists and antagonists on food intake and/or appetite.     

Effects of intracerebroventricular injections of free fatty acids, lysophospholipids, or platelet activating factor in a mouse model of orofacial pain

The present study was carried out to determine the effects of central nervous free fatty acids, lysophospholipids, or platelet activating factor (PAF), in a mouse facial carrageenan injection model of orofacial pain. Mice that received intracerebroventricular (I.C.V.) injection of arachidonic acid or oleic acid showed significantly reduced allodynia and behavioral responses to von Frey hair stimulation of a carrageenan-injected area of the face, at 8 h post-injection, compared to controls that received I.C.V. injection of vehicle. In contrast to free fatty acids, increased responses were observed in mice at 72 h after I.C.V. lysophosphatidic acid or lysophosphatidylcholine injection, and at 8 and 24 h after PAF injection, compared vehicle injected controls. Information regarding pro-nociceptive effect of specific brain lipids may be a useful basis for further studies to explore mechanism.     

Long-term normalization of blood pressure in SHR and 1-kidney 1-clip rats by synthetic precursor of stable PAF analogue without systemic effects in normotensive rats

This study characterized the actions of the newly synthesized PAF precursor 1-hexadecyl-2-alkylcarbamoyl-glycerol (HAG) on blood pressure (BP) in male spontaneously hypertensive rats (SHR), SHR-stroke prone (SHRSP) and Wistar rats with 1-kidney 1-clip (1K1C) renovascular hypertension used as experimental models of human primary and secondary hypertension. Systolic blood pressure (SBP) in the tail artery and mean arterial pressure (MAP) in the abdominal aorta were measured by tail plethysmography and invasive pressure transducer, respectively. Intravenous treatment with 1 mg/kg HAG in SHR resulted in a rapid decline of MAP from 151 ± 4 to 127 ± 4 mm Hg in 50 min (p < 0.001) that was maintained for 24 h after injection (128 ± 5 mm Hg, p < 0.01). We also observed a profound hypotensive effect of HAG in SHRSP but not in normotensive Wistar rats. In 1K1C rats, the magnitude of the BP decline evoked by HAG was correlated with MAP measured before drug administration (R = 0.74, p < 0.005). In 1K1C rats with SBP > 140 mm Hg, 5 mg/kg/48 h HAG, given orally for 14 days, decreased SBP by 20-30 mm Hg without an increase in the death rate and other adverse effects. Thus, our results show that intravenous and oral administration of HAG led to a long-lasting reduction of BP in experimental models of primary and secondary hypertension. In contrast to PAF and its derivatives, the hypotensive action of HAG was preserved for 24 h after a single administration, was absent in normotensive animals, and was not accompanied by visible side-effects, at least during 2 weeks of treatment.