ABSTRACT
The aim of this study was to evaluate the effects of streptozotocin-induced type 1diabetes and a subchronic treatment with cyclohexanonic long-chain fatty alcohol, 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen 1-one (tCFA15) on contents of amino acids including aspartate, glutamate, glutamine, GABA, glycine, taurine, alanine, serine, threonine, and arginine in the prefrontal cortex, hippocampus and striatum. Levels of glutamate, threonine, taurine, alanine, arginine, and the ratio of glutamate/glutamine were altered region-differently in the brain of diabetic rats. However, tCFA15 region-specifically antagonized the changes in taurine and arginine levels and the ratio of glutamate/glutamine. The alteration in glutamate/glutamine ratio may indicate that experimental models of type 1 diabetes have abnormalities of neuron-gria interaction in brain.
Subject(s)
Amino Acids/metabolism , Brain Chemistry/drug effects , Cyclohexanones/pharmacology , Diabetes Mellitus, Experimental/metabolism , Fatty Alcohols/pharmacology , Animals , Blood Glucose/metabolism , Body Weight/drug effects , Chromatography, High Pressure Liquid , Insulin/blood , Male , Rats , Rats, Sprague-DawleyABSTRACT
We studied the effects of cyclohexenonic long-chain fatty alcohol (N-hexacosanol) on diabetes-induced angiopathy in the rat aorta. Male Sprague-Dawley rats were divided into 4 groups, a control group and 3 other groups in which diabetes was induced by streptozotocin (50 mg/kg i.p.). Four weeks after the induction of diabetes, the 3 groups received treatment with either vehicle or N-hexacosanol (2 or 8 mg/kg, i.p. every day) for another 4 weeks. To determine the mechanisms of diabetic vascular dysfunction and the effects of N-hexacosanol, we conducted organ bath studies and real-time polymerase chain reaction on muscarinic M(3) receptor, and endothelial and inducible nitric oxide synthase (eNOS and iNOS) mRNAs in the rat aorta. Treatment with N-hexacosanol did not alter the diabetic status, but improved the diabetes-induced hypercontraction produced by norepinephrine and the damaged endothelium-dependent relaxation of the rat aorta induced by acetylcholine. Furthermore, in the diabetic rats, both muscarinic M(3) receptor and iNOS mRNAs were significantly increased, and N-hexacosanol reversed these upregulations. However, the expression of eNOS mRNA showed no change in all groups. These results indicate that N-hexacosanol has beneficial effects on functional dysfunction and reverses the upregulation of muscarinic M(3) receptor and iNOS mRNAs in the diabetic rat aorta.
Subject(s)
Aorta, Thoracic/drug effects , Diabetic Angiopathies/drug therapy , Fatty Alcohols/therapeutic use , Animals , Aorta, Thoracic/metabolism , Aorta, Thoracic/physiopathology , Diabetes Mellitus, Experimental/complications , Diabetic Angiopathies/metabolism , Diabetic Angiopathies/physiopathology , In Vitro Techniques , Male , Muscle Contraction , Muscle Relaxation , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/metabolism , Muscle, Smooth, Vascular/physiopathology , Nitric Oxide Synthase Type II/biosynthesis , Nitric Oxide Synthase Type II/genetics , Nitric Oxide Synthase Type III/biosynthesis , Nitric Oxide Synthase Type III/genetics , RNA, Messenger/biosynthesis , Rats , Rats, Sprague-Dawley , Receptor, Muscarinic M3/biosynthesis , Receptor, Muscarinic M3/geneticsABSTRACT
OBJECTIVES: We investigated the ability of 3-(15 hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen 1-one (N-hexacosanol), a neurotrophic substance, to reverse diabetes-induced cystopathy in the rat. MATERIALS AND METHODS: Eight-week-old male Sprague-Dawley rats were divided randomly into four age-matched groups. In three of these groups, diabetes was induced by streptozotocin (STZ; 50mg/kg intraperitoneal [IP]). Four weeks after the induction of diabetes, the three groups received another 4 weeks of treatment by vehicle or N-hexacosanol (2 or 8 mg/kg IP every day). The serum glucose and serum insulin levels were determined, and the bladder functions were estimated by voiding behavior studies, cystometric studies, and functional studies using carbachol and KCl. The participation levels of M(2) and M(3) receptors were investigated by real-time polymerase chain reaction and immunohistochemical staining. Typical hematoxylin-eosin staining was also performed. RESULTS: Treatment with N-hexacosanol did not alter the rats' diabetic status, but did significantly improve the diabetes-induced dysfunction of the detrusor in a dose-dependent manner. Furthermore, N-hexacosanol significantly reversed the upregulation of muscarinic M(2) and M(3) receptor messenger RNAs (mRNAs) in STZ-diabetic rats. Muscarinic M(2) and M(3) receptors were localized in detrusor and urothelium, and there was no difference between any of the groups in the distribution of muscarinic M(2) and M(3) receptors. CONCLUSIONS: These results indicate that N-hexacosanol has a beneficial effect on hyperreactivity in the diabetic detrusor by ameliorating overexpression of muscarinic M(2) and M(3) receptor mRNAs.
Subject(s)
Cyclohexanones/therapeutic use , Diabetes Complications/drug therapy , Fatty Alcohols/therapeutic use , Urinary Bladder Diseases/drug therapy , Animals , Male , Rats , Rats, Sprague-DawleyABSTRACT
In this study, we investigated the preventive effect of n-hexacosanol on diabetes-induced bladder dysfunction in the rat. Diabetes was induced in 8-week-old male Sprague-Dawley rats by administering an injection of streptozotocin (50 mg/kg, i.p.). The rats were randomly divided into 4 groups (age-matched control rats, diabetic rats without treatment with n-hexacosanol, and diabetic rats treated with n-hexacosanol (2 and 8 mg/kg, i.p. every day)) and maintained for 4 weeks. The serum glucose and serum insulin levels were determined, and the functions of bladder were estimated by voiding behavior, cystometric, and functional studies to carbachol and KCl. Furthermore, we examined possible diabetic induced histological changes in these rats. Treatment with n-hexacosanol did not alter diabetic status including body mass, bladder mass, and serum glucose and serum insulin levels, but significantly improved the maximum contraction pressure of the detrusor and residual urine volume in cystometric studies and Emax values to carbachol in functional studies in a dose-dependent manner. Diabetes induced bladder smooth muscle hypertrophy, which tended to be ameliorated by treatment with n-hexacosanol in a dose-dependent manner. Treatment with n-hexacosanol did not alter the diabetic status, but significantly improved diabetic cystopathy in a dose-dependent manner.
Subject(s)
Diabetes Mellitus, Experimental/prevention & control , Fatty Alcohols/therapeutic use , Urinary Bladder Diseases/prevention & control , Animals , Cyclohexanes/pharmacology , Cyclohexanes/therapeutic use , Cyclohexenes , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/pathology , Fatty Alcohols/pharmacology , Male , Rats , Rats, Sprague-Dawley , Urinary Bladder/drug effects , Urinary Bladder/metabolism , Urinary Bladder/pathology , Urinary Bladder Diseases/metabolism , Urinary Bladder Diseases/pathology , Urination/drug effects , Urination/physiologyABSTRACT
In this study we investigated the effects of N-hexacosanol on streptozotocin-induced rat diabetic nephropathy. Diabetes was induced in 8-week-old male Sprague-Dawley rats by administering an intraperitoneal injection of streptozotocin (50 mg/kg). The rats were divided into four groups and maintained for 8 weeks: control rats, diabetic rats without treatment with N-hexacosanol, and diabetic rats treated with N-hexacosanol (2 mg/kg and 8 mg/kg i.p. every day). Although N-hexacosanol failed to modify the diabetic status, increases in serum creatinine as well as in kidney weight were significantly reduced. The malonaldehyde and transforming growth factor beta-1 (TGF-beta1) concentrations as well as the protein kinase C (PKC) activities in the diabetic kidney were significantly higher than those of the control, which were decreased by treatment with N-hexacosanol. Histological examinations revealed that N-hexacosanol significantly ameliorated diabetic-induced tubulointerstitial pathological changes. Our data suggest that N-hexacosanol could prevent increases in the malonaldehyde and TGF-beta1 concentrations and PKC activities in the kidney, and ameliorate diabetic-induced nephropathy.
Subject(s)
Diabetic Nephropathies/chemically induced , Diabetic Nephropathies/pathology , Fatty Alcohols/pharmacology , Streptozocin/pharmacology , Animals , Blood Urea Nitrogen , Creatinine/metabolism , Insulin/metabolism , Male , Malondialdehyde/metabolism , Protein Kinase C/metabolism , Rats , Rats, Sprague-Dawley , Transforming Growth Factor beta1/metabolismABSTRACT
Diabetic neuropathy, a major complication of diabetes mellitus, is associated with development of gastrointestinal motility dysfunction and autonomic neuropathy. N-hexacosanol has neurotrophic effects and exhibits a wide variety of biological actions. In this study, we investigated the effects of cyclohexenonic long-chain fatty alcohol (N-hexacosanol) on streptozotocin-diabetic hypercontractility in the rat ileum longitudinal muscles. Treatment with N-hexacosanol did not alter the diabetic status of the animals, i.e., body weight, serum glucose, and serum insulin levels, but significantly restored the thickness of intestine wall and ameliorated diabetes-induced hypercontractility of the rat ileum in a dose-dependent manner. Furthermore, N-hexacosanol reversed the diabetes-induced upregulation of intestinal muscarinic M(2) and M(3) receptors mRNAs in the streptozotocin-diabetic rats. These results indicate that N-hexacosanol has therapeutic effects on hypercontractility in the diabetic ileum by ameliorating overexpression of muscarinic M(2) and M(3) receptors mRNAs.
Subject(s)
Diabetes Mellitus, Experimental/physiopathology , Diabetic Neuropathies/drug therapy , Fatty Alcohols/pharmacology , Ileum/drug effects , Muscle Contraction/drug effects , Receptor, Muscarinic M2/drug effects , Receptor, Muscarinic M3/drug effects , Animals , Calcium/metabolism , Fatty Alcohols/therapeutic use , Ileum/physiopathology , Male , Rats , Rats, Sprague-Dawley , Receptor, Muscarinic M2/genetics , Receptor, Muscarinic M3/genetics , StreptozocinABSTRACT
In the present study, we attempted to clarify the role of nitric oxide (NO) and its release during the ischemia-reperfusion rat testis. Eight-week-old male Sprague-Dawley rats were divided into seven groups: age-matched control rats, ischemia (30 minutes)-reperfusion (30 minutes) rats without NG-nitro-L-arginine methyl ester (L-NAME) and L-arginine (L-Arg) treatment, ischemia (30 minutes)-reperfusion (30 minutes) rats treated with L-NAME (10, 30, and 100 mg/kg), ischemia-reperfusion rats treated with L-Arg (10 and 30 mg/kg). Sixty minutes prior to induction of ischemia, L-NAME or L-Arg was administrated intraperitoneally. Real-time monitoring of blood flow and NO release were measured simultaneously with a laser Doppler flowmeter and an NO-selective electrode, respectively. NO2-NO3 and malonaldehyde (MDA) concentrations were measured in the experimental testes. Furthermore, we investigated possible morphological changes in the testis. Clamping of the testicular artery decreased blood flow to 5-20% of the basal level measured before clamping. Immediately following clipping of the artery, NO release rapidly increased. After removing the clip, NO release gradually returned to the basal level. This phenomenon was enhanced by treatment with L-Arg and inhibited by treatment with L-NAME. NO2-NO3 concentrations were increased by treatment with L-Arg and decreased by treatment with L-NAME, while MDA concentrations were increased by treatment with L-NAME and were decreased by treatment with L-Arg. In histological studies, the ischemia-reperfusion caused infiltration of leukocytes and a rupture of microvessels in the testis. Our data suggest that NO has cytoprotective effects on ischemia-reperfusion injury in the rat testis.
Subject(s)
Monitoring, Physiologic/methods , Nitric Oxide/metabolism , Reperfusion Injury/physiopathology , Testis/metabolism , Animals , Arginine/administration & dosage , Arginine/pharmacology , Blood Flow Velocity/drug effects , Blood Flow Velocity/physiology , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/pharmacology , Laser-Doppler Flowmetry , Male , Malondialdehyde/metabolism , NG-Nitroarginine Methyl Ester/administration & dosage , NG-Nitroarginine Methyl Ester/pharmacology , Nitrates/metabolism , Nitric Oxide Synthase/antagonists & inhibitors , Nitrites/metabolism , Rats , Rats, Sprague-Dawley , Testis/blood supply , Testis/drug effects , Time FactorsABSTRACT
Narp (neuronal activity-regulated pentraxin) is a secreted immediate early gene product functioning as a cluster factor for the AMPA receptor subtype of glutamate receptors. This study was designed to examine the effects of acute administration of methamphetamine (MAP) on the Narp gene in rat brain using reverse transcription - polymerase chain reaction (RT-PCR). Acute administration of MAP [4.6 mg/kg, intraperitoneally (i.p.)] increased Narp mRNA in the prefrontal cortex, whereas the same treatment with MAP decreased Narp mRNA in the hippocampus. Therefore, Narp gene could be involved in the MAP-induced effects.
