Therapeutic activity of plant-derived alkaloid conophylline on metabolic syndrome and neurodegenerative disease models.

Increasing metabolic syndromes including type-2 diabetes mellitus, obesity, and steatohepatitis are serious problems in most countries in the world. Neurodegenerative diseases such as Alzheimer, Parkinson's, and Huntington's diseases are increasing in many countries. However, therapy for these diseases is not sufficient yet. Thus, effective chemotherapy for these diseases is being expected. Conophylline is an alkaloid isolated from the leaves of Ervatamia microphylla and related plants. It was found to induce beta-cell differentiation in the precursor pancreatic cells. Oral administration of this compound ameliorated type-2 diabetes mellitus model in mice and rats. Later, fibrosis of the pancreatic islets was found to be greatly reduced by conophylline in the pancreatic islets. It also inhibited chemically induced liver cirrhosis. Further study indicated that conophylline inhibited non-alcoholic steatohepatitis in the model mice. On the one hand, loss of autophagy often causes protein aggregation to give neural cell death. Conophylline was found to activate autophagy in cultured neural cells. Activation of autophagy ameliorated cellular models of Parkinson's and Huntington's diseases. Thus, conophylline is likely to be useful for the development of chemotherapy for metabolic and neurodegenerative diseases.

Angiotensin II type 1 receptor antagonist prevents hepatic carcinoma in rats with nonalcoholic steatohepatitis.

BACKGROUND: Angiotensin II type 1 receptor blockers (ARBs) have been reported to attenuate hepatic fibrosis in non-alcoholic steatohepatitis (NASH). However, it is uncertain whether ARBs prevent hepatocarcinogenesis in NASH even after hepatic fibrosis has developed. METHODS: Male Wistar rats were fed with a choline-deficient, L-amino acid-defined (CDAA) diet for 24 weeks, and then fed with the CDAA diet with telmisartan (2 mg/kg/day), a novel ARB, or vehicle for another 24 weeks. The liver histology and the expression of genes and proteins related to angiogenesis were investigated. RESULTS: The 24-week CDAA diet induced liver cirrhosis. The 48-week CDAA diet exacerbated liver cirrhosis, and developed hepatocellular carcinoma (HCC) in 54.6 % of the rats concurrently with increases of hypoxia-inducible factor-1α (HIF-1α) protein and vascular endothelial growth factor (VEGF) mRNA, which are potent angiogenic factors in the liver. Telmisartan inhibited hepatic fibrosis and preneoplastic lesions and prevented the development of HCC along with inducing decreases in HIF-1α protein and VEGF mRNA. CONCLUSIONS: These data indicated that telmisartan may prevent hepatocarcinogenesis through the inhibition of hepatic angiogenesis even after liver cirrhosis has been established.

Electroacupuncture elicits dual effects: stimulation of delayed gastric emptying and inhibition of accelerated colonic transit induced by restraint stress in rats.

Acupuncture has been used for treating functional gastrointestinal (GI) disorders. Animal studies have demonstrated that acupuncture antagonized various stress-induced responses. We investigated the effects of electroacupuncture (EA) at ST-36 (Zusanli; lower limb) on stress-induced alteration of GI motor activities. Solid gastric emptying was significantly delayed by restraint stress (29.6+/-2.4%; n=7) compared to that of controls (60.0+/-2.5%; n=8). Delayed gastric emptying was significantly improved by EA at ST-36 (47.2+/-1.8%). Intracisternal (IC) injection of corticotropin releasing factor (CRF; 1 microg) delayed gastric emptying to 25.4+/-3.1%, which was also improved by EA at ST-36, to 53.0+/-7.1% (n=8). The stimulatory effect of EA on stress-induced delayed gastric emptying was abolished by atropine (17.6+/-1.9%) but not by guanethidine (42.2+/-2.3%). Colonic transit was significantly accelerated by restraint stress (GC=7.2+/-0.3; n=8) compared to that of controls (GC=5.2+/-0.2; n=8). Accelerated colonic transit was significantly reduced by EA at ST-36 (GC=4.9+/-0.3). IC injection of CRF accelerated colonic transit (GC=6.9+/-0.2), which was also normalized by EA at ST-36 (GC=4.7+/-0.2). The inhibitory effect of EA on stress-induced acceleration of colonic transit was not affected by guanethidine (GC=4.6+/-0.3). In conclusion, EA at ST-36 showed dual effects: stimulation of stress-induced delayed gastric emptying and inhibition of stress-induced acceleration of colonic transit. The stimulatory effect of EA on stress-induced delayed gastric emptying is mediated via cholinergic pathways. The inhibitory effect of EA on stress-induced acceleration of colonic transit is independent of the sympathetic pathway.

Electroacupuncture improves restraint stress-induced delay of gastric emptying via central glutaminergic pathways in conscious rats.

Acupuncture has been used for treating functional gastrointestinal (GI) disorders. Animal studies demonstrated that acupuncture improves various stress-induced physiological responses. We investigated the effects of electroacupuncture (EA) at ST-36 (Zusanli; lower limb) on stress-induced delay of gastric emptying. Solid food gastric emptying in 90 min was significantly delayed by restraint stress (27.3 +/- 2.1%, n = 8), compared to that of controls (64 +/- 2.1%, n = 8). Restraint stress-induced delay of gastric emptying was significantly restored by the intracisternal (IC)-injection of GABA(A) receptor antagonist, bicuculline methiodide (46.5 +/- 3.1%; n = 6) and GABA(B) receptor antagonist, phaclofen (48 +/- 3.3%; n = 6). Delayed gastric emptying induced by restraint stress was significantly improved by EA at ST-36 (49.7 +/- 1.4%). The stimulatory effect of EA on stress-induced delay of gastric emptying was prevented by pretreatment with IC-injection of glutamate receptor antagonist, kynurenic acid (30.1 +/- 2.1%). In conclusion, restraint stress-induced delay of gastric emptying is mediated via central GABA(A) and GABA(B) receptors. EA at ST-36 stimulates glutaminergic neurons in the brainstem resulting in improvement of stress-induced delay of gastric emptying.

Electroacupuncture at ST-36 accelerates colonic motility and transit in freely moving conscious rats.

Acupuncture is useful for functional bowel diseases, such as constipation and diarrhea. However, the mechanisms of beneficial effects of acupuncture on colonic function have scarcely ever been investigated. We tested the hypothesis that electroacupuncture (EA) at ST-36 stimulates colonic motility and transit via a parasympathetic pathway in conscious rats. Hook-shaped needles were inserted at bilateral ST-36 (lower limb) or BL-21 (back) and electrically stimulated at 10 Hz for 20 min. We also studied c-Fos expression in response to EA at ST-36 in Barrington's nucleus of the pons. EA at ST-36, but not BL-21, significantly increased the amplitude of motility at the distal colon. The calculated motility index of the distal colon increased to 132 +/- 9.9% of basal levels (n = 14, P < 0.05). In contrast, EA at ST-36 had no stimulatory effects in the proximal colon. EA at ST-36 significantly accelerated colonic transit [geometric center (GC) = 6.76 +/- 0.42, n = 9, P < 0.001] compared with EA at BL-21 (GC = 5.23 +/- 0.39, n = 7). The stimulatory effect of EA at ST-36 on colonic motility and transit was abolished by pretreatment with atropine. EA-induced acceleration of colonic transit was also abolished by extrinsic nerve denervation of the distal colon (GC = 4.69 +/- 0.33, n = 6). The number of c-Fos-immunopositive cells at Barrington's nucleus significantly increased in response to EA at ST-36 to 8.1 +/- 1.1 cells/section compared with that of controls (2.4 +/- 0.5 cells/section, n = 3, P < 0.01). It is concluded that EA at ST-36 stimulates distal colonic motility and accelerates colonic transit via a sacral parasympathetic efferent pathway (pelvic nerve). Barrington's nucleus plays an important role in mediating EA-induced distal colonic motility in conscious rats.

Electroacupuncture reduces rectal distension-induced blood pressure changes in conscious dogs.

It has been shown that acupuncture relieves symptoms of abdominal pain and bloating in patients with irritable bowel syndrome (IBS). However, the mechanism of beneficial effects of acupuncture still remains unproven. The aim of the present study was to investigate the mechanisms of the antinociceptive effects of acupuncture in conscious dogs. We evaluated the increase in mean arterial blood pressure (MAP) caused by rectal distension as an index of visceral pain. Electroacupuncture (EA; 10 Hz) at ST-36 (lower leg), but not at BL-21 (back), significantly reduced the increase in MAP in response to rectal distension (30 and 40 cm3). The antinociceptive effect of EA at ST-36 was abolished by pretreatment with naloxone (a central and peripheral opioid receptor antagonist) but not by naloxone methiodide (a peripheral opioid receptor antagonist). These results suggest that EA at ST-36 may reduce visceral pain via central opioid pathway. Acupuncture may be useful to treat visceral hypersensitivity in IBS patients.