Octreotide-mediated neurofunctional recovery in rats following traumatic brain injury. Role of H2S, Nrf2 and TNF-α

ABSTRACT Purpose: To explore the role and mechanisms of octreotide in neurofunctional recovery in the traumatic brain injury (TBI) model. Methods: Rats were subjected to midline incision followed by TBI in the prefrontal cortex region. After 72 hours, the behavioural and neurological deficits tests were performed, which included memory testing on Morris water maze for 5 days. Octreotide (15 and 30 mg/kg i.p.) was administered 30 minutes before subjecting to TBI, and its administration was continued for three days. Results: In TBI-subjected rats, administration of octreotide restored on day 4 escape latency time (ELT) and increased the time spent in the target quadrant (TSTQ) on day 5, suggesting the improvement in learning and memory. It also increased the expression of H2S, Nrf2, and cystathionine-γ-lyase (CSE) in the prefrontal cortex, without any significant effect on cystathionine-β-synthase. Octreotide also decreased the TNF-α levels and neurological severity score. However, co-administration of CSE inhibitor (D,L-propargylglycine) abolished octreotide-mediated neurofunctional recovery, decreased the levels of H2S and Nrf2 and increased the levels of TNF-α. Conclusions: Octreotide improved the neurological functions in TBI-subjected rats, which may be due to up-regulation of H2S biosynthetic enzyme (CSE), levels of H2S and Nrf2 and down-regulation of neuroinflammation.

Beneficial effects of octreotide in alcohol-induced neuropathic pain. Role of H 2S, BDNF, TNF-α and Nrf2

ABSTRACT Purpose To explore the role and molecular mechanisms of neuroprotective effects of octreotide in alcohol-induced neuropathic pain. Methods Male Wistar rats were employed and were administered a chronic ethanol diet containing 5% v/v alcohol for 28 days. The development of neuropathic pain was assessed using von Frey hair (mechanical allodynia), pinprick (mechanical hyperalgesia) and cold acetone drop tests (cold allodynia). The antinociceptive effects of octreotide (20 and 40 µg·kg-1) were assessed by its administration for 28 days in ethanol-treated rats. ANA-12 (0.25 and 0.50 mg·kg-1), brain-derived neurotrophic factor (BDNF) receptor blocker, was coadministered with octreotide. The sciatic nerve was isolated to assess the biochemical changes including hydrogen sulfide (H2S), cystathionine β synthase (CBS), cystathionine γ lyase (CSE), tumor necrosis factor-α (TNF-α), BDNF and nuclear factor erythroid 2-related factor 2 (Nrf2). Results Octreotide significantly attenuated chronic ethanol-induced neuropathic pain and it also restored the levels of H2S, CBS, CSE, BDNF, Nrf2 and decreased TNF-α levels. ANA-12 abolished the effects of octreotide on pain, TNF-α, BDNF, Nrf2 without any significant effects on H2S, CBS, CSE. Conclusions Octreotide may attenuate the behavioral manifestations of alcoholic neuropathic pain, which may be due to an increase in H2S, CBS, CSE, BDNF, Nrf2 and a decrease in neuroinflammation.

Primary octreotide LAR therapy in GH-secreting pituitary adenoma.

A case of a 54-year-old male with active acromegaly and severe aortic stenosis treated primarily with octreotide LAR 20 mg/ IM/month for six months is reported here. His serum growth hormone level declined and was sustained throughout the period of six months (basal GH level 21.8 ng/ml; 1.2 ng/ml six months after therapy; mean+/-SD during six months of therapy 1.36+/-0.34 ng/ml; range 0.9 - 1.9 ng/ml). The post-treatment, postgadolinium, T1 weighted sagittal magnetic resonance images showed disappearance of the growth hormone secreting adenoma. The use of octreotide LAR as primary therapy in active acromegaly is discussed along with a brief review of literature.

Successful Treatment of Protein-Losing Enteropathy Induced by Intestinal Lymphangiectasia in a Liver Cirrhosis Patient with Octreotide: A Case Report

A 47-yr-old man with hepatitis B virus associated liver cirrhosis was admitted to our hospital with diarrhea and generalized edema and diagnosed as protein-losing enteropathy due to intestinal lymphangiectasia by intestinal biopsy and 99mTc albumin scan. During hospitalization, he received subcutaneous octreotide therapy. After 2 weeks of octreotide therapy, follow-up albumin scan showed no albumin leakage, and the serum albumin level was sustained. We speculate that liver cirrhosis can be a cause of intestinal lymphangiectasia and administration of octreotide should be considered for patients with intestinal lymphangiectasia whose clinical and biochemical abnormalities do not respond to a low-fat diet.

Exogenous cysteamine increases basal pancreatic exocrine secretion in the rat

To determine whether exocrine pancreatic secretion is regulated by endogenous somatostatin, somatostatin deficiency was induced by cysteamine. Rats were subcutaneously administered a single dose of cysteamine (30 mg/100 g body weight) 12 hr before experiment. Anesthetized rats were prepared with cannulation into bile duct, pancreatic duct, duodenum, and jugular vein and pancreatic juice was collected. For in vitro study, isolated pancreata of rats, pretreated with cysteamine, were perfused with an intraarterial infusion of Krebs-Henseleit solution (37 degrees C) at 1.2 mL/min, and pancreatic juice was collected in 15-min samples. In vivo experiment of the rat, the mean basal pancreatic secretions, including volume, bicarbonate, and protein output were significantly increased from 18.4+/-0.5 microL/30 min, 0.58+/-0.05 microEq/30 min, and 214.0+/-26.1 microg/30 min to 51.6+/-3.7 microL/30 min, 1.52+/-0.11 microEq/30 min, and 569.8+/-128.9 microg/30 min, respectively (p<0.05). In the isolated perfused pancreas, cysteamine also resulted in a significant increase in basal pancreatic secretion (p<0.05). Simultaneous intraarterial infusion of octreotide (10 pmol/hr) to isolated pancreata partially reversed the effect of cysteamine on basal pancreatic secretion. These findings suggest that endogenous somatostatin play an important role on the regulation of basal pancreatic exocrine secretion.

Octreotide: a clinical update

Somatostatin is found in the pancreas and gastrointestinal tract, including the visceral autonomic nervous system, the endocrine D cells and the gut lumen. Somatostatin peptides may act differently at different sites as hormones, as paracrine substances or neurotransmitters. So far not much is known on the physiological effects of somatostatin in the gastrointestinal tract. Somatostatin and octreotide, a synthetic analogue with a longer half-life and higher potency, inhibit the neuroendocrine and exocrine gastrointestinal secretion, intestinal glucose, fat and amino acid transport, intestinal propulsive and gallbladder motility, splanchnic blood flow in volunteers and hepatic venous pressure in cirrhotic patients. The inhibition occurs to various extents depending on the target organ. This review deals with the pharmacological effects of octreotide on different gastrointestinal functions and describes the therapeutic role in different gastrointestinal disorders

Octreotide (SMS 201-995) as an antisecretory agent in cholera toxin & bile acid induced intestinal secretion in an in vivo animal study.

The effect of Octreotide (SMS 201-995), synthetic somatostatin analogue on small intestinal and colonic fluid secretion induced respectively by cholera toxin (CT) and deoxycholic acid (DCA) was investigated in rabbits using in vivo isolated loops. After exposure to CT and DCA, marked fluid accumulation was observed in the small intestinal and colonic loops, along with elevation of jejunal and colonic mucosal cyclic AMP concentrations. Octreotide inhibited CT and DCA induced small intestinal and colonic secretion, dose-dependently. This anti-secretory effect was observed after both intramuscular and oral administration of octreotide. In contrast, octreotide did not affect the elevated mucosal cyclic AMP concentrations. These results suggest that octreotide inhibits CT and DCA induced intestinal secretion, and this anti-secretory effect is produced by affecting processes beyond cyclic AMP formation.

Effect of the somatostatin analogue octreotide (SMS201-995) on portal and mesenteric blood flow in rats

Várias investigaçöes revelaram que a somatostatina e análogas baixam o fluxo sanguíneo esplâncnico e portal em cirróticos e em modelos experimentais de hipertensäo portal. Tem sido experimentado habitualmente no tratamento de varizes sangrantes. O mecanismo pelo qual o hormônio age permanece obscuro. No presente estudo investigou-se o efeito da açäo prolongada do octreotide, somatostatina análoga, no fluxo sanguíneo mesentérico e portal, em ratos sadios. A administraçäo intravenosa do octreotide näo teve efeito significante na circulaçäo esplânic. Em alguns animais registrou-se, após a infusäo inicial da droga, queda pequena no fluxo venoso portal. Infusöes adicionais näo alteraram o fluxo portal. O fluxo sangüíneo mesentérico superior permaneceu inalterado. Conclui-se que o octreotide näo influiu na circulaçäo espâncnica, em ratos sadios, e que novos estudos se fazem necessários para explicar os seus efeitos em modelos de hipertensäo portal

Effect of long-term administration of somatostatin analogue on renal enlargement in uninephrectomized-diabetic rats

Recent study has demonstrated that the long-acting somatostatin analogue administration effectively prevented initial renal growth in diabetic and uninephrectomized rats. In the present study we examined long-term effect of somatostatin analogue (Sandostatin) on renal enlargement in uninephrectomized-diabetic rat5. Animals were divided into 4 groups: (1) normal control rats (C) (n = 7), (2) uninephrectomized rats (NPX) (n = 7), (3) uninephrectomized-diabetic rats (NPX + DM) (n = 7) and (4) NPX + DM rats treated with Sandostatin (NPX + DM + Tx) (n = 9). All animals had free access to diet (50% protein) and water during the experimental period. To the NPX + DM + Tx rats, 2.5 micrograms of Sandostatin was given subcutaneously twice a day for 8 weeks. Periodic observations were done at 0, 4 and 8 weeks. After 8 weeks. NPX rats (0.540 +/- 0.017 (SEM)) had higher fractional kidney weights (FKW) (wet kidney wt/body wt) compared to C rats (0.410 +/- 0.014) (p < 0.0005), and both NPX + DM rats (0.983 +/- 0.098) and NPX + DM + Tx rats (1.091 +/- 0.042) had higher FKW compared to C rats (p < 0.0001) and NPX rats (p < 0.005), respectively. But no significant change of FKW was observed between NPX + DM rats and NPX + DM + Tx rats. Systolic blood pressure, BUN, serum creatinine, glomerular filtration rate and 24 hour urine protein excretion in NPX + DM rats were not different from those in NPX + DM + Tx rats.(ABSTRACT TRUNCATED AT 250 WORDS)