Non-technical summary Systemic inflammation and related disorders, including sepsis, are leading causes of death in hospitalized patients. In most severe cases, systemic inflammation is accompanied by a drop in body temperature (hypothermia). We know that inflammation-associated hypothermia is a brain-mediated response, but mechanisms of this response are unknown. We administered a bacterial product (endotoxin) to rats to cause systemic inflammation and hypothermia. We then used a variety of pharmacological tools to probe whether three different receptors are involved in this hypothermia. We have found that one of the receptors studied, the so-called cannabinoid-1 (CB1) receptor, is crucial for the development of hypothermia. This is the same receptor that is responsible for many effects of marihuana (cannabis). We further show that hypothermia associated with inflammation depends on CB1 receptors located inside the brain. These novel findings suggest that brain CB1 receptors should be studied as potential therapeutic targets in systemic inflammation and sepsis.Abstract Hypothermia occurs in the most severe cases of systemic inflammation, but the mechanisms involved are poorly understood. This study evaluated whether the hypothermic response to bacterial lipopolysaccharide (LPS) is modulated by the endocannabinoid anandamide (AEA) and its receptors: cannabinoid-1 (CB1), cannabinoid-2 (CB2) and transient receptor potential vanilloid-1 (TRPV1). In rats exposed to an ambient temperature of 22• C, a moderate dose of LPS (25-100 μg kg −1 I.V.) induced a fall in body temperature with a nadir at ∼100 min postinjection. This response was not affected by desensitization of intra-abdominal TRPV1 receptors with resiniferatoxin (20 μg kg −1 I.P.), by systemic TRPV1 antagonism with capsazepine (40 mg kg −1 I.P.), or by systemic CB2 receptor antagonism with SR144528 (1.4 mg kgHowever, CB1 receptor antagonism by rimonabant (4.6 mg kg −1 I.P.) or SLV319 (15 mg kgblocked LPS hypothermia. The effect of rimonabant was further studied. Rimonabant blocked LPS hypothermia when administered I.C.V. at a dose (4.6 μg) that was too low to produce systemic effects. The blockade of LPS hypothermia by I.C.V. rimonabant was associated with suppression of the circulating level of tumour necrosis factor-α. In contrast to rimonabant, the I.C.V. administration of AEA (50 μg) enhanced LPS hypothermia. Importantly, I.C.V. AEA did not evoke hypothermia in rats not treated with LPS, thus indicating that AEA modulates LPS-activated pathways in the brain rather than thermoeffector pathways. In conclusion, the present study reveals a novel, critical role of brain CB1 receptors in LPS hypothermia. Brain CB1 receptors may constitute a new therapeutic target in systemic inflammation and sepsis.

Arachidonic acid (ARA) is a major component of lipid bilayers as well as the key substrate for the eicosanoid cascades. ARA is readily oxidized, and its non-enzymatic and enzymatic oxidation products induce inflammatory responses in nearly all tissues, including lung tissues. Deuteration at bis-allylic positions substantially decreases the overall rate of ARA oxidation when hydrogen abstraction is an initiating event. To compare the effects of dosing of arachidonic acid (H-ARA) and its bis-allylic hexadeuterated form (D-ARA) on lungs in conventionally healthy mice and in an acute lung injury model, mice were dosed with H-ARA or D-ARA for six weeks through dietary supplementation and then challenged with intranasal lipopolysaccharide (LPS) for subsequent analysis of bronchoalveolar lavage fluid and lung tissue. Dosing on D-ARA resulted in successful incorporation of D-ARA into various tissues. D-ARA significantly reduced LPS-induced adverse effects on alveolar septal thickness and the bronchoalveolar area. Oral deuterated ARA is taken up efficiently and protects against adverse LPS-induced pathology. This suggests novel therapeutic avenues for reducing lung damage during severe infections and other pathological conditions with inflammation in the pulmonary system and other inflammatory diseases.

Objective. To estimate an anti-nociceptive and regenerative potential of adipose-derived mesenchymal stem cells in experimental post-traumatic neuropathy in rats. Methods. Neuropathic pain was induced by axotomy technique in rat left hind paw (Wistar rats (n=113)). The respective group of subjects received ADMSCs dose of 1×10⁶ cells/kg and 2×10⁶ cells/kg into the site of sciatic nerve injury at 2 regimens: single (7^th day post-surgery) and twice (7^th and 14^th day post-surgery). Nociceptive responses, as well as histological changes of sciatic nerve and perineural tissue were assessed in dynamics. Results. Sciatic nerve axotomy led to a significant increase of mechanical nociceptive sensitivity of ipsilateral hind paw by 7^th day, as well as to fibrotic changes of peri- and epineural areas of damaged nerve fibers and to denervation of surrounding muscle tissue and fascia. Local administration of ADMSCs effectively abolished mechanical hyperalgesia by 14^th day after first injection at all regimens tested. Among tested regimens, the most pronounced anti-nociceptive and regenerative effects were induced by single injection of ADMSCs (1×10⁶ cells/kg). As the dose and frequency of ADMSCs administration elevated, their reparative and anti-inflammatory properties reduced. Conclusion. Obtained results testify anti-nociceptive potential of ADMSCs and feasibility of its further investigation on the experimental models of neuropathy. What this paper adds For the first time the impact of different regimen of allogenic adipose-derived mesenchymal stem cells (ADMSCs) transplantation on nociceptive sensitivity and microstructure changes of sciatic nerve in rats with peripheral neuropathy has been studied. Allogenic transplantation of mesenchymal stem cells at a dose of 1×10⁶ cells/kg has been found out to exhibit the most powerful anti-nociceptive and regenerative effects with a single local injection confirmed by algometry and histological study.

Республика БеларусьЦель. Изучить ранозаживляющие свойства N-пальмитоилэтаноламина и N-стеароилэтаноламина в липосомальной форме, сравнить их действие с лекарственным средством с доказанной эффективностью.Материал и методы. Ранозаживляющее влияние N-пальмитоилэтаноламина и N-стеароилэтаноламина изучено на 214 белых рандомбредных крысах-самцах с тремя типами кожных ран: линейные, лоскутные и ожоговые. Для исследования каждого типа ран животные были разделены на группы: контрольная (раны не обрабатывались), отрицательный контроль (или растворитель), положительный контроль (мазь Метилу-рацил), пальмитоилэтаноламин и стеароилэтаноламин. Ежедневно проводили мониторинг общего состо-яния животных, фотосъемку ран. После этого поверхность ран обрабатывали исследуемыми веществами. Обработку ран продолжали до полного заживления с фиксированием суток заживления. Выводы делали на основании результатов визуального наблюдения, компьютерной планиметрии, данных морфологического исследования.Результаты. В случае применения обоих N-ацилэтаноламинов сокращение сроков заживления ли-нейных ран не зафиксировано, длительность периода заживления составила 8-10 суток. Лоскутные раны в контрольных группах заживали в течение 21-25 суток. В случае применения N-стеароилэтаноламина этот показатель составил 22-25 суток (p>0,05). Напротив, ежедневная аппликация пальмитоилэтаноламина на поверхность лоскутных ран приводила к их заживлению на 18-19 сутки (p<0,05). Термические ожоги IIIА степени в контрольных группах заживали в течение 30-32 суток. Применение обоих N-ацилэтаноламинов приводило к уменьшению этого срока до 27-28 суток, в случае N-стеароилэтаноламина эти изменения были достоверными (p<0,05).Заключение. N-пальмитоилэтаноламин и N-стеароилэтаноламин в липосомальной форме оказывают стимулирующее воздействие на регенерацию раневых дефектов кожи. Пальмитоилэтаноламин сокращает сроки заживления лоскутных кожных ран, N-стеароилэтаноламин ускоряет заживление ожоговых ран. N-ацилэтаноламины в липосомальной форме являются перспективными для использования в качестве ранозаживляющих средств. Дальнейшие исследования в этом направлении могут стать научной основой создания новых фармацевтических средств. Ключевые слова: ацилэтаноламин, липосомы, кожные раны, регенерация, эпидермис, дерма, ранозажив-ляющие свойства, создание новых фармацевтических средствObjectives. To study wound-healing properties of N-palmitoylethanolamine and N-stearoylethanolamine in liposomes and to compare their action with the drug has also proven to be an effective and safe.Methods. The wound-healing effects of N-palmitoylethanolamine and N-stearoylethanolamine were studied on white male rats (n=214) with three types of skin wounds: incision, excision and burn wounds. To study each type of wounds the animals were divided into groups: control (untreated wounds), negative control (or solvent), positive control (Methyluracil ointment), N-palmitoylethanolamine and N-stearoylethanolamine. The general state of animals was monitored daily; all wounds were photographed and then treat...

Peripheral neuropathy is associated with chronic debilitating pain and is difficult to treat. In this regard, the development of cell therapy of neuropathic pain using adipose-derived mesenchymal stem cells (MSCs) seems to be relevant.The work was devoted to study the impact of adipose-derived allogeneic MSC transplantation on nociceptive reactions in response to mechanical and thermal stimuli and gait parameters in rats with sciatic nerve injury.It is found that a single local injection of MSCs at a dose of 1·106 cells/kg eliminates axotomy-induced mechanical and thermal hyperalgesia on the 14th day after transplantation, contributes to the recovery of the sciatic functional index and the dynamic gait parameters on the 7th day after transplantation, and prevents the development of gait disturbances in the long-term period.

No abstract

Назначение медикаментозной терапии остеопороза и немедикаментозных мер профилактики падений и переломов является краеугольным камнем в предотвращении травматизации и инвалидизации пожилого населения. По разным данным, даже после случившегося низкотравматического перелома лечение причиныостеопороза -назначается всего 20% пациентам [1][2][3][4]. Эти данные показывают, что упускается множество возможностей по предупреждению будущих переломов. В качестве причин такой слабой инициации лечения обсуждаются многие факторы (табл. 1). Так, считается, что пробел в терапии находится между лечением случившегося низкоэнергетического перелома и предупреждением будущих переломов. Отдельного внимания заслуживает врачебный фактор, а именно -нехватка времени врача, незнание проблемы остеопороза, сложности в назначении лечения остеопороза.До недавнего времени назначение антиостеопоротической терапии проводилось в основном за счет личных средств пациента. И только небольшая доля пациентов в настоящее время имеют возможность получить лечение бесплатно за счет льготного обеспечения (рис. 1).

Objective. Compare the effectiveness of systemic and local administration of adipose-derived mesenchymal stem cells (ADMSC) at a dose of 1х106 cells/kg on nociceptive sensitivity to mechanical and thermal stimuli in rats and changes in histostructure of sciatic nerve and surrounded tissues of affected hind paw in experimental model of peripheral neuropathy of sciatic nerve.Materials and methods. 26 male Wistar rats were used to perform a model of peripheral neuropathy by axotomy of the sciatic nerve. On the 7th day, the experimental animals underwent systemic or local transplantation of ADMSC at a dose of 1x106 cells/kg. Nociceptive responses to mechanical and thermal stimuli were assessed for 90 days, and the histostructure of the sciatic nerve and surrounding tissues was analyzed after systemic and local transplantation of ADMSC.Results. Systemic administration of ADMSC at a dose of 1x106 cells/kg to rats with sciatic nerve axotomy increased the mechanical withdrawal threshold (MWT) by 17.1% and had no effect on the thermal withdrawal latency (TWL). Local administration of ADMSCs in an equivalent dose contributed to the full recovery of the MWT and TWL by the 21st day of the experiment, as well as suppressed the inflammatory reaction in the soft tissues of the operated hind paw of experimental animals.Conclusion. Intramuscular administration of ADMSC into the area of sciatic nerve axotomy of rats was significantly more effective than systemic administration of an equivalent dose of a cell transplant. This method of administration is more appropriate for further studies of the mechanisms of antinociceptive and reparative effects of ADMSCs.