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New antidiabetic agent succibun protects from diabetes mellitus type 1 development in mice
THE EFFECT OF CALCIUM CHANNEL BLOCKERS AND 1NDOMETHACIN ON INSULIN SECRETION DERIVED FROM ALPHA- 1 AND BETA ADRENOCEPTOR STIMULATION IN THE RABBIT M.J~Garcia-Barrado. J. Palomero, J. Moratinos. Department of Physiology and Pharmacology. School of Medicine. Av/Campo Charro s/n 37007. Salamanca. Spain. In conscious fasted rabbits the i-v infusion of amidephrine (~-1 agonist, 3 or 10 jag/kg/min for 30 min), induced a dose related increase of immunoreactive insulin plasma levels (peak effect, 52.2925.82%, n=5, p<0.001 and 115.80+_36.40%, n=7, p<0.001 vs -2.90+2.86%, n=7 saline treated animals). The ~-1 mediated response was suppressed in rabbits pretreated with calcium channd blockers (a at 45 min in the absence and presence of verapamil, 0.17 ~tg/kg/min, or elgodipine, 35 ng/kg/min, respectively were 115.80+36.40%, n=7, vs 19.26+6.28, n=7, p<0.001 and 28.30+26.95%, n=8, p<0.001). In animals pretreated with indomethacin (0.66 mg/kg/min) the effect evoked by the higher dose of amidephrine was abolished (A at 45 min, -13.77 +14.23%, n=5, p<0.001). As the ability of amidephrine to increase circulating insulin was shown in the absence of haemodynamic alterations, being atropine resistant, it is possible to suggest that the c,-1 mediated effect is a direct one requiring the presence of extracellular calcium and,the synthesis of an arachidonic acid metabolite. In addition the insulin secretory rise mediated by isoprenaline ([~-agonist, at 0.3 gg/kg/min i-v for 30 min) was similarly blunted by elgodipine (A at 45 min in the absence and presence of elgodipine, 112.30+24.37%, n=6, vs 11.44+9.42, n=4, p<0.001 respectively) confirming a relationship between the adenylate cyclase system and calcium fluxes in the beta-cell.
NOVEL ANTIOXIDANT PHENSUCCINALPREVENTS THE DIABETIC MICROVASCULAR COMPLICATIONS IN RATS N.Gorbenko, V~Poltorack, L.Piv0varevich, v,Lipson, T.Ovsyanikova and O.Borodina Ukralnian Scientific Research Institute of Endocrine Diseases Pharmacotherapy, Artyoma Str.,10, 310002 Kharkov, Ukraine. We have previosly shown that the new lowtoxic compound phensuccinal (P):beta-phenylethylamide-2-hydroxysuccinanylic acid possesses antioxidant effect due to free radical scavenging activity a n d s t i m u l a t i o n of glutathione peroxidase. The aim of the present study was to explore the influence of P on the microangiopathy development and oxidative status in rats w i t h non-insulindependent diabetes mellitus (NIDDM). The newborn ( 2-3 days) rats were given streptozotocin (STZ) (i00 mg/kg, i.p.). One group of diabetic animals was untreated to act as control. The other group received~P (25 mg/kg/day) in the diet for 3 months. The treatment rats with p decreased basal hyperglycemia by 30%. increased plasma insulin level and improved glucose tolerance.Antioxidant effect of P was assessed in liver homogenate by spectrophotometric determination of malonic dialdehyde (MDA), vitamins A, E and carotenoids. After 3 months treatment with P MDA were reduced 2.5 fold in comparison with control. It has been shown P to increase vitamins A and carotenoids contents, but not vitamin E concentration. Histological examination of kidney revealed protective effect of P on microvascular complications development in diabetic rats.We suggest that P c o u l d be a useful agent for the treatment of NIDDM microvascular complications.
EFFECT OF ALDOSE REDUCTASE INHIBITION ON BRAIN NEUROTRANSMISSION OF GALACTOSEMIC RATS T. Kuchmerovskava, P. Parkhomets, N. Kuehmerovsky, A. Klimenko,I. Ol~rosova, L. Pakyrbayeva, G. Donchenko and A.Yefimov Institute of Biochemistry, Leontovich Street, 9, 252030 Kiev, Ukraine.
NEW ANTIDIABETIC AGENT SUCCIBUN PROTECTS FROM DIABETES MELLITUS TYPE 1 DEVELOPMENT IN MICE V.Poltorack, V.Natarov, N.Gorbenko, V.Lipson, A,Gladkich and V.Petruck Ukrainian Scientific Research Institute of Endocrine Diseases Pharmacotherapy, Artyoma Str.,10, 310002 Kharkov, Ukraine.
Aldose reductase (AR) is a key enzyme of the polyol pathway. The study was aimed at evaluating whether blocking the conversion of galactose to galactatiol by the AR inhibitor, AL-01576 affects neurotransmitters uptake and release by isolated brain cortex synap}cosomes and neurotransmitters binding whith isolated synaptic me~branes f galactosemic rats. The findings showed that 2- Cse rotonin uptake was 37% lowered while u34CGABA uptake was 49% inereased in galactosemic rats as compared to controls (p<0.05). The galactosemic rats (70% galactose diet for 30 days) demonstrated the increased neurotransmitter release. AL-01576 administration (4 m g / k g body weight dailly i.m. for 14 days) to galactosemic rats was accompanied by the partial restoration of 2-t4eserotonin and U-14CGABA uptake by isolated brain cortex synaptosomes to t h a t in controls. It was established that serotonin, dopamine and GABA binding was altered significantly. It was shown that neurotransmitters binding was restored by AL-01576. The effects of in vivo administered AL-01576 to galactosemic rats appeared to be to diabetic rats similar, suggesting that the polyol pathway played an important role in the. regulation of glucose metabolism.
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A new oral hypoglycemic agent Succibun (S): l-[4-N-butylureasulfonyl(phenyl)]pyrrolidin- 2,5-dione was found to suppress humoral immunity to sheeps erythrocytes in BALB/c mice. The aim of study was to evaluate effect of S on the insulin-dependent diabetes m e l l i t u s (IDDM) development. Males BALB/c mice were glven streptozotocin (STy) (50 mg/kg/ day x 5, i.p.). One group of animals was treated with S ( 50 mg/kg per os for 2 weeks) begining on the next day after the last STZ-injection. Control diabetic mice were glven water alone. The treatment w i t h S protected against basal hyperglycemia development (p
NOVEL ANTIOXIDANT PHENSUCCINALPREVENTS THE DIABETIC MICROVASCULAR COMPLICATIONS IN RATS N.Gorbenko, V~Poltorack, L.Piv0varevich, v,Lipson, T.Ovsyanikova and O.Borodina Ukralnian Scientific Research Institute of Endocrine Diseases Pharmacotherapy, Artyoma Str.,10, 310002 Kharkov, Ukraine. We have previosly shown that the new lowtoxic compound phensuccinal (P):beta-phenylethylamide-2-hydroxysuccinanylic acid possesses antioxidant effect due to free radical scavenging activity a n d s t i m u l a t i o n of glutathione peroxidase. The aim of the present study was to explore the influence of P on the microangiopathy development and oxidative status in rats w i t h non-insulindependent diabetes mellitus (NIDDM). The newborn ( 2-3 days) rats were given streptozotocin (STZ) (i00 mg/kg, i.p.). One group of diabetic animals was untreated to act as control. The other group received~P (25 mg/kg/day) in the diet for 3 months. The treatment rats with p decreased basal hyperglycemia by 30%. increased plasma insulin level and improved glucose tolerance.Antioxidant effect of P was assessed in liver homogenate by spectrophotometric determination of malonic dialdehyde (MDA), vitamins A, E and carotenoids. After 3 months treatment with P MDA were reduced 2.5 fold in comparison with control. It has been shown P to increase vitamins A and carotenoids contents, but not vitamin E concentration. Histological examination of kidney revealed protective effect of P on microvascular complications development in diabetic rats.We suggest that P c o u l d be a useful agent for the treatment of NIDDM microvascular complications.
EFFECT OF ALDOSE REDUCTASE INHIBITION ON BRAIN NEUROTRANSMISSION OF GALACTOSEMIC RATS T. Kuchmerovskava, P. Parkhomets, N. Kuehmerovsky, A. Klimenko,I. Ol~rosova, L. Pakyrbayeva, G. Donchenko and A.Yefimov Institute of Biochemistry, Leontovich Street, 9, 252030 Kiev, Ukraine.
NEW ANTIDIABETIC AGENT SUCCIBUN PROTECTS FROM DIABETES MELLITUS TYPE 1 DEVELOPMENT IN MICE V.Poltorack, V.Natarov, N.Gorbenko, V.Lipson, A,Gladkich and V.Petruck Ukrainian Scientific Research Institute of Endocrine Diseases Pharmacotherapy, Artyoma Str.,10, 310002 Kharkov, Ukraine.
Aldose reductase (AR) is a key enzyme of the polyol pathway. The study was aimed at evaluating whether blocking the conversion of galactose to galactatiol by the AR inhibitor, AL-01576 affects neurotransmitters uptake and release by isolated brain cortex synap}cosomes and neurotransmitters binding whith isolated synaptic me~branes f galactosemic rats. The findings showed that 2- Cse rotonin uptake was 37% lowered while u34CGABA uptake was 49% inereased in galactosemic rats as compared to controls (p<0.05). The galactosemic rats (70% galactose diet for 30 days) demonstrated the increased neurotransmitter release. AL-01576 administration (4 m g / k g body weight dailly i.m. for 14 days) to galactosemic rats was accompanied by the partial restoration of 2-t4eserotonin and U-14CGABA uptake by isolated brain cortex synaptosomes to t h a t in controls. It was established that serotonin, dopamine and GABA binding was altered significantly. It was shown that neurotransmitters binding was restored by AL-01576. The effects of in vivo administered AL-01576 to galactosemic rats appeared to be to diabetic rats similar, suggesting that the polyol pathway played an important role in the. regulation of glucose metabolism.
- - 87 - -
A new oral hypoglycemic agent Succibun (S): l-[4-N-butylureasulfonyl(phenyl)]pyrrolidin- 2,5-dione was found to suppress humoral immunity to sheeps erythrocytes in BALB/c mice. The aim of study was to evaluate effect of S on the insulin-dependent diabetes m e l l i t u s (IDDM) development. Males BALB/c mice were glven streptozotocin (STy) (50 mg/kg/ day x 5, i.p.). One group of animals was treated with S ( 50 mg/kg per os for 2 weeks) begining on the next day after the last STZ-injection. Control diabetic mice were glven water alone. The treatment w i t h S protected against basal hyperglycemia development (p