Combined administration of anisodamine and neostigmine rescued acute lethal crush syndrome through α7nAChR-dependent JAK2-STAT3 signaling.

Previously we showed that Ani (anisodamine)/Neo (neostigmine) combination produced anti-shock effect via activating α7 nicotinic acetylcholine receptor (α7nAChR). In this study, we aim to investigate the therapeutic effect and underlying mechanisms of Ani/Neo combination in acute lethal crush syndrome (CS). In rat and rabbit CS models, Ani/Neo combination increased the 24 h survival rates, improved hemodynamics and decreased the levels of creatine kinase, MB isoenzyme of creatine kinase, blood urea nitrogen, creatinine, K+ in serum. It also decreased the levels of H2O2, myeloperoxidase (MPO) and nitric oxide (NO) in serum and compressed muscle in rat CS model. In wild-type (WT) mice with CS, Ani/Neo combination increased 24 h survival rate and decreased the levels of H2O2, MPO, NO, TNFα, IL-6 and IL-10 in compressed muscle. These effects were attenuated by α7nAChR knockout (KO). Moreover, Ani/Neo combination prevented the decrease of phosphorylation of Janus kinase 2 (JAK2) and phosphorylation of signal transducer and activator of transcription 3 (STAT3) induced by CS. These effects of Ani/Neo in CS mice were cancelled by methyllycaconitine (α7nAChR antagonist) and α7nAChR KO. Collectively, our results demonstrate that Ani/Neo combination could produce therapeutic effects in CS. The underlying mechanism involves the activation of α7nAChR-dependent JAK2-STAT3 signaling pathway.

Improved angiogenesis and healing in crush syndrome by fibroblast growth factor-2-containing low-molecular-weight heparin (Fragmin)/protamine nanoparticles.

BACKGROUND: We produced fibroblast growth factor (FGF)-2-containing low-molecular-weight heparin (Fragmin)/protamine nanoparticles (FGF-2 + F/P NPs). The purpose of this study was to evaluate the effectiveness of the local administration of FGF-2 + F/P NPs on repairing crush syndrome (CS)-injured lesions after compression release using a nonlethal and reproducible CS injury rat model. MATERIALS AND METHODS: The hind limbs of the anesthetized rats were compressed for 6 h using 3.6 kg blocks, as previously described. The effects of administering FGF-2 + F/P NPs (group A), F/P NPs alone (group B), FGF-2 alone (group C), and saline (control; group D) were examined. Motor function, surface blood flow in the hind limbs, and the wet/dry weight ratio in the tibialis anterior muscle were examined for 1-28 d after the compression release. Histologic analyses were also performed. RESULTS: At the middle and late stages (3-28 d after the compression release), group A had higher scores in the motor function, improved blood flow, increased number of blood vessels, and faster recovered muscle tissue, compared with the other groups. There was no significant difference in enhanced edema in the tibialis anterior muscle among all groups. CONCLUSIONS: The local administration of FGF-2 + F/P NPs to a CS-injured lesion was effective in repairing damaged muscle tissue after compression release.

Sivelestat improves outcome of crush injury by inhibiting high-mobility group box 1 in rats.

Severe crush injury is associated with high mortality because of resulting hyperkalemia in early phase and multiorgan dysfunction in later phase. In this study, we investigated the effects of sivelestat administration 1 h before reperfusion on the outcome of crush injury. Crush injury was induced by 6 h of direct compression to both hindlimbs of anesthetized rats with blocks weighing 3.5 kg each side, followed by 3 h of reperfusion. Rats were randomly assigned to three groups. In the control group, rats were infused with normal saline at 1 mL/kg per hour throughout the experiment without compression. Rats in the positive control group were compressed for 6 h, followed by fluid resuscitation initiated 1 h before release with normal saline. The infusion rate was increased from 1 to 10 mL/kg per hour and continued for 4 h. Rats in the treated group underwent the same procedures as in the positive control group, but sivelestat was added to normal saline (concentration was adjusted to infuse 10 mg/kg per hour) during fluid resuscitation (for 4 h). Treatment with sivelestat significantly improved survival rate with P = 0.032. This was accompanied by lower serum high-mobility group box 1 (HMGB1) levels after 3-h reperfusion, attenuated lung injury (assessed using hematoxylin-eosin stain), and suppression of HMGB1 expression in the lung and the liver. These results suggest that treatment with sivelestat improves the outcome of crush injury, likely by inhibiting HMGB1 in rats.

Effect of ginkgo biloba extract on recovery after facial nerve crush injury in the rat.

BACKGROUND AND OBJECTIVE: Many pharmacological agents have shown successful results in experimental crush injury of the peripheral nerve. To date, therapeutic effect of ginkgo biloba extract (GBE) on the peripheral nerve crush injury of rats has been rarely reported, moreover, neuroprotective effect on the facial nerve crush injury has not been reported. MATERIALS AND METHODS: Prospective functional recovery, using a vibrissae movement and electrophysiological analysis of recovery 4 weeks after the facial nerve crush in adult rats, and comparison with randomized intraperitoneal injection of either GBE or control phosphate buffered saline. RESULTS: Relative to the control group (26 days post operation), administration of GBE significantly accelerated the recovery of vibrissae orientation to 11.7 days post the operation. A significant functional recovery was observed by postoperative 2nd week in the experimental group. The recovery of threshold and conduction velocity, postoperative 4th week in the experimental group, showed statistically significant difference compared to that of the control group. CONCLUSION: From this result, intraperitoneal injection of GBE has been found effective in promoting the regeneration of the nerve in an experimental facial nerve crush rat model. Further studies, including morphological and molecular analyses, are necessary to clarify the mechanisms of GBE on the facial nerve crush.

[Treatment for crush syndrome of extremities with antioxidants].

OBJECTIVE: To study the clinical therapeutic effect of antioxidants assistant treatment of extremities crush syndrome (CS)in order to find new therapy. METHODS: Twenty-one male patients (aged from 24 to 48 years, mean 36 years) were treated with the next antioxidants in early stage: (1) 20% Mannitol 250 ml intravenous drip in 30 minutes (one time per 6 to 8 h). (2) Sodium aescinate 20 mg, Salvia Miltiorrhiza 20 ml were dissolved respectively in isotonic saline or 5% glucose 200 ml and dripped by intravenous drip (50 to 60 drips per minute). The drugs were used for 5 to 7 days (one time per day). Basifying urine, keeping the nagative liquid banlance and electrolyte banlance, preventing infection and hold out treatment were done. When the pressure of muscular osteofascial compartment was more than 30 mmHg, deep fasia was cut to decompress timely and the above-mentioned drugs were continuously applied for patients. RESULTS: Myoglobin urine of 21 cases died out after 2 to 3 days, of them, 13 cases were performed to decompress. After open decompression, 2 cases suffered from amputation because of long time of ischemia, 2 cases took place slight dysfunction of lower limbs, one hand had ischemia muscular contracture in 1 case and one foot down-vertical in 1 case. After followed-up of 8 months to 1 year, according to the function standard, the result were excellent in 8 cases, good in 7 cases, fair in 2 cases, poor in 4 cases. The excellent and good rate was about 71.4% (15/21). CONCLUSION: After extremities crushed for long time, application of antioxidents as early as possible can decrease significantly the incidence and invalidity rate of CS.

The repair effects of Achyranthes bidentata extract on the crushed common peroneal nerve of rabbits.

In this study the effect of the Achyranthes bidentata root aqueous extract on regeneration of the crushed common peroneal nerve in rabbits by using a combination of electrophysiological assessment and histological aspect were investigated. The examined functional and morphological parameters suggest that A. bidentata extract could accelerate peripheral nerve regeneration in a dose-dependent manner (10-20 microg/kg, i.v.).

Proline-rich polypeptides in Alzheimer's disease and neurodegenerative disorders -- therapeutic potential or a mirage?

The development of effective and safe drugs for a growing Alzheimer disease population is an increasing need at present. Both experimental and clinical evidence support a beneficial effect of proline-rich polypeptides in a number of neurodegenerative diseases, including Alzheimer disease. Experimental data have shown that proline-rich polypeptides isolated from bovine neurohypophisis possess neuroprotective and neuromodulatory properties in mice with aluminum neurotoxicosis or neuronal damage caused by venoms and toxins. Proline-rich polypeptides from ovine colostrums, so called Colostrinin, have been shown to produce cognitive improvement in an experimental model and in patients with Alzheimer disease. However, the precise mechanism underlying the neuroprotective action of proline-rich polypeptides is not very well established. Moreover, studies pointing at a neuroprotective effect of proline-rich polypeptides from bovine neurohypophisis in humans have not been reported thus far. The authors conclude that more detailed information on the mode of action of proline-rich polypeptides is needed as well as confirmation of their efficacy in broad clinical trials before this approach can really show its potential in the treatment of neurodegenerative disorders.

[Phytin efficacy in correction of the impaired detoxication liver function in the long-term compression syndrome in rats in prepubertal period]. / Effektivnost' fitina v korreltsii narushenii detoksitsiruiushchei funktsii pecheni krys pri sindrome dlitel'nogo sdavlivaniia v prepubertatnom periode.

The compression syndrome was reproduced in rats aged one month and the efficacy of phytin in correcting the activity infringement and restoring the content of basic components of the hepatocyte monooxygenase enzyme system was studied in the postcompression period. The compression led to pronounced inhibition of the activity of aniline hydroxylase and amidopyrine M-demethylase, reduced the content of liver microsomal protein and cytochromes P-450 and b5, and increased the level of medium- molecular-weight (MMW) peptides in the blood serum. A six-day treatment with phytin restored the normal level of the liver monooxygenase system components and MMW peptides. Phytin reduced the level of lactic acid (LA) and increased that of pyruvic acid (PA) in liver tissues, which led to a sharp drop in the LA/MA ratio indicative of a decrease in the extent of hypoxia.

[Experimental prostaglandin E2 therapy of acute kidney failure due to the crush syndrome]. / Eksperimental'naia terapiia prostaglandinom E2 ostroi pochechnoi nedostatochnosti, vyzvannoi krash-sindromom.

It has been shown for the first time that intraaortal injection of PGE2 to dogs with acute renal failure caused by the crush syndrome makes renal function (glomerular filtration, tubular reabsorption, renal plasmaflow, maximal tubular secretion, minute and diurnal diuresis) return to normal.

[Use of liposomes as a nonspecific detoxifier in the crush syndrome]. / Ispol'zovanie liposom v kachestve nespetsificheskogo detoksikatora pri sindrome dlitel'nogo razdavlivaniia.

The possibility of parenteral detoxification was studied in dogs with the experimental crush syndrome. Infusion of lecithin liposomes (25 and 50 mg/kg) prevented the development of postcompression toxemia and hemodynamic disorders characteristic for endogenous intoxication. The use of the nonspecific parenteral sorbent lecithin liposomes permitted the maintenance of an adequate function of the animals' cardiovascular system for 5 hours after decompression.

[Effect of serotonin on the lysosomal apparatus of liver cells and on hydrolase activity in the blood in severe mechanical injury]. / Vliianie serotonina na lizosomal'nyi apparat kletok pecheni i aktivnost' gidrolaz v krovi pri tiazheloi mekhanicheskoi travme.

A study was made of the pattern of changes in overall and non-sedimented activity of lysosomal hydrolases of the liver of rats injected with serotonin under grave mechanical trauma. Lability of the lysosomal membranes was found to be twice as increased, with remarkable hyperfermentemia being seen starting from the 3rd hour of compression in the presence of an appreciable rise of overall enzymatic activity. The role of serotonin in the mechanism of exocytosis of lysosomal enzymes is discussed.