Neurobio-logy of multiple myeloma and its therapeutical use - results of the pilot study with a control arm.

BACKGROUND: Myeloma cells, occupying a bone marrow niche, are influenced not only by neighbouring stroma cells but also by signals from the axons of sympathetic nervous system. The nervous system is directly involved in the process of myeloma progression. Among other cancers, patients with myeloma suffer the most difficult distress generating intensive adrenergic signals, causing its further progression. There is a question arising from these facts regarding whether psychological interventions, modulating a function of the nervous system, can further improve outcomes of myeloma treatments. We focus on interactions between myeloma cells and the nervous system. PATIENTS AND METHODS: Twelve patients with monoclonal gamapathy of indetermined significance (MGUS) or myeloma have participated in this study; eight in the interventional arm with the intervention of forgiveness therapy and four in the control arm. The patients were in various phases of their treatment, from active observation to immuno-chemotherapy and autologous stem cell transplant. Two major types of parameters were measured during the intervention: parameters of the activity of the disease (MGUS or myeloma) and psycho-neuro-immunological parameters of the patient, such as psychological depression, anxiety, and anger by the validated test PROMIS), as well as activity of the autonomic nervous system by heart rate variability, and immune profile by flow cytometry of peripheral blood. RESULTS: Patients who completed the forgiveness intervention showed improvement of depression, anxiety, and anger measured by PROMIS above population average, significant expansion of physiological plasma cells CD138+38+ (P = 0.04), B memory lymphocytes CD27+ (P = 0.02), and dendritic plasmacytoid cells CD123+ (P = 0.03). Parameters of heart rate variability such as parasympatic nervous system (PNS) index, sympatic nervous system (SNS) index, stress index, standard deviation of NN intervals (SDNN) and root mean square of the successive differences (RMSSD) had improved in a majority of patients. CONCLUSION: An intervention centered on forgiveness therapy was able to improve distress, reduce adrenergic signals in the autonomic nervous system, and restore parameters of the immune profile of patients with plasma cell dyscrasia who suffered from chronic stress caused by repressed anger and unforgiveness. Integrative treatment of myeloma can improve the quality of life of patients and thus affect the efficiency of immuno-chemotherapy. New randomised trials are warranted to test the integrative treatment of myeloma that might be able to improve overall survival.

Neurobiology of cancer - the role of cancer tissue innervation.

BACKGROUND: Experimental and clinical studies have shown that the nervous system also plays an important role in the processes of carcinogenesis, cancer cell proliferation, and metastasis. These studies, focused on the neurobio-logical aspects of cancer, elucidate the mechanisms and pathways by which the nervous system affects tumor macro- and microenvironment. The modulatory effect of the nervous system on the tumor microenvironment is significantly mediated by nerves that innervate cancer tissue. The innervation of cancer tissue is already an accepted fact, and several authors consider it to be another hallmark of cancer. PURPOSE: The aim of this review article is to present a recent data about the role of innervation of cancer tissue, as well as to describe therapeutic consequences. CONCLUSION: Based on recent data, it can be concluded that the innervation of cancer tissue represents an important factor in the etiopathogenesis of cancer as well as a potential target for new therapeutic interventions in cancer patients.

Role of the parasympathetic nervous system in cancer initiation and progression

The nervous system plays an important role in cancer initiation and progression. Accumulated evidences clearly show that the sympathetic nervous system exerts stimulatory effects on carcinogenesis and cancer growth. However, the role of the parasympathetic nervous system in cancer has been much less elucidated. Whereas retrospective studies in vagotomized patients and experiments employing vagotomized animals indicate the parasympathetic nervous system has an inhibitory effect on cancer, clinical studies in patients with prostate cancer indicate it has stimulatory effects. Therefore, the aim of this paper is a critical evaluation of the available data related to the role of the parasympathetic nervous system in cancer (AU)

Role of the parasympathetic nervous system in cancer initiation and progression.

The nervous system plays an important role in cancer initiation and progression. Accumulated evidences clearly show that the sympathetic nervous system exerts stimulatory effects on carcinogenesis and cancer growth. However, the role of the parasympathetic nervous system in cancer has been much less elucidated. Whereas retrospective studies in vagotomized patients and experiments employing vagotomized animals indicate the parasympathetic nervous system has an inhibitory effect on cancer, clinical studies in patients with prostate cancer indicate it has stimulatory effects. Therefore, the aim of this paper is a critical evaluation of the available data related to the role of the parasympathetic nervous system in cancer.

Effect of the nervous system on cancer: Analysis of clinical studies.

Preclinical data have shown that neurotransmitters released in peripheral tissues from nerve endings may influence carcinogenesis, affect the tumor microenvironment, and directly potentiate both proliferation and migration of cancer cells. This stimulatory role of the nervous system in cancer initiation and progression has also been documented by clinical studies investigating the effect of attenuated signaling from nerves innervating cancer tissue. However, compared to preclinical studies, clinical studies are rarer and some of them have ambiguous results. In this retrospective analysis, to assess the effect of the nervous system on cancer, we analyzed published clinical studies investigating the incidence of cancer in patients with spinal cord injury or pheochromocytoma. Our findings support a concept of the neurobiology of cancer based on the assumption that the nervous system affects cancer initiation and progression (Ref. 60). Keywords: cancer, neurobiology of cancer, norepinephrine, sympathetic nervous system, spinal cord injury, pheochromocytoma.

Oxytocin Modulates Expression of Neuron and Glial Markers in the Rat Hippocampus.

Neuropeptides including oxytocin belong to the group of factors that may play a role in the control of neuronal cell survival, proliferation and differentiation. The aim of the present study was to investigate potential contribution of oxytocin to neuronal differentiation by measuring gene and protein expression of specific neuron and glial markers in the brain. Neonatal and adult oxytocin administration was used to reveal developmental and/or acute effects of oxytocin in Wistar rats. Gene and protein expression of neuron-specific enolase (NSE) in the hippocampus was increased in 21-day and 2-month old rats in response to neonatal oxytocin administration. Neonatal oxytocin treatment induced a significant increase of gene and protein expression of the marker of astrocytes - glial fibrillary acid protein (GFAP). Oxytocin treatment resulted in a decrease of oligodendrocyte marker mRNA - 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) - in 21-day and 2-month old rats, while no change of CD68 mRNA, marker of microglia, was observed. Central oxytocin administration in adult rats induced a significant increase of gene expression of NSE and CNPase. The present study provides the first data revealing the effect of oxytocin on the expression of neuron and glial markers in the brain. It may be suggested that the oxytocin system is involved in the regulation of development of neuronal precursor cells in the brain.

Prefrontal cortex and dorsomedial hypothalamus mediate food reward-induced effects via npas2 and egr1 expression in rat.

The effects of food reward on circadian system function were investigated in the hypothalamic nuclei, prefrontal cortex and liver. Food rewards of small hedonic and caloric value were provided for 16 days 3 h after light phase onset to male Wistar rats. The daily pattern of locomotor activity was monitored. Gene expression profiling performed in the dorsomedial hypothalamus (DMH) and liver at the time of reward delivery indicated transcriptional factors egr1 and npas2 as possible mediators of food reward effects. Candidate genes were measured in the suprachiasmatic nuclei (SCN), DMH, arcuate nucleus (ARC), prefrontal cortex (PFC) and liver along with per2 expression. A daily pattern in glycemia and per2 expression in the SCN was emphasized by food reward. The expression of egr1 was rhythmic in the SCN, DMH, PFC and liver and food reward weakened or diminished this rhythm. The expression of npas2 was rhythmic in all tissues except for the PFC where food reward induced rhythm in npas2 expression. Food reward induced npas2 and egr1 expression in the DMH at the time of reward delivery. We suppose that the DMH and PFC participate in the adjustment of the circadian system to utilize food reward-induced input via egr1 and npas2 expression.

Effect of the autonomic nervous system on cancer progression depends on the type of tumor: solid are more affected then ascitic tumors.

OBJECTIVES: A number of recently published studies have shown that the sympathetic nervous system may influence cancer progression. There are, however, some ambiguities about the role of the parasympathetic nerves in the modulation of growth of different tumor types. Moreover, tumor models used for investigation of the autonomic neurotransmission role in the processes related to the cancer growth and progression are mainly of the solid nature. The knowledge about the nervous system involvement in the modulation of the development and progression of malignant ascites is only fragmental. Therefore, the aim of the present article was to summarize the results of our experimental studies focused on the elucidation of the role of the autonomic nervous system in the modulation of tumor growth in animals. We are summarizing data from studies, in which not only different experimental approaches in order to influence the autonomic neurotransmission, but also different tumor models have been used. METHODS: Three different types of tumor models, namely solid rat intra-abdominal fibrosarcoma, solid murine subcutaneous melanoma, and rat ascites hepatoma, and three types of interventions have been used in order to modulate the autonomic neurotransmission, specifically chemical sympathectomy, subdiaphragmatic vagotomy, or the electric stimulation of the vagus nerve. RESULTS: We have proved a strong stimulatory effect of the sympathetic nerves on the development and growth in both solid tumors, rat fibrosarcoma as well as murine melanoma, and significant inhibitory impact on the survival time of tumor-bearing animals. The progression of ascites hepatoma in rats was not influenced by chemical sympathectomy. Modulation of parasympathetic signalization by vagotomy or vagal nerve stimulation does not affect fibrosarcoma and ascites hepatoma growth and survival of the tumor-bearing rats. CONCLUSIONS: Based on the obtained data, it seems that the solid types of tumors are suitable substrate for the direct action of neurotransmitters released especially from the sympathetic nerves. In contrast, it appears that the malignant ascites are not under the direct autonomic nerves control; however, an indirect action via the immune functions modulation cannot be excluded.

Sympathectomized tumor-bearing mice survive longer but develop bigger melanomas.

OBJECTIVES: Previously we have shown that 20 days after the tumor cells injection smaller melanomas have been developed in chemically sympathectomized mice in comparison with animals having intact sympathetic nervous system. However, it is known that chemical sympathectomy reduces the sympathetic neurotransmission only temporarily. In the present study, we monitored the survival of the sympathectomized mice with melanoma with an attempt to find out how long the suppressing effect of sympathectomy on the melanoma growth may endure. METHODS: The chemical sympathectomy was performed by intraperitoneal injection of neurotoxin 6-hydroxydopamine in male C57BL/6J mice. Seven days later, the animals were injected subcutaneously with B16-F10 melanoma cells. Then, melanoma development, survival of the tumor-bearing mice and weight of the developed tumor mass were analyzed. RESULTS: Sympathectomy delayed the development of the palpable tumors (18th day vs.14th day) and significantly prolonged the survival of the tumor-bearing mice (median 34 days vs. 29 days). However, the weight of the developed melanoma was significantly increased in the sympathectomized mice in comparison with the animals having intact sympathetic nervous system. CONCLUSIONS: The data of the present study showed that effect of the chemical sympathectomy, performed before the tumor growth induction, persisted even at the time when sympathetic nerves started to regenerate that resulted in a prolonged survival of the mice with melanoma. However, comparing to our previous study, in which we have shown a reduced tumor mass in earlier stages of the tumor growth, specifically 20 days after melanoma cells injection, now we indicate that in later stages of the melanoma progression, the tumor mass was significantly increased in sympathectomized animals. These contra-intuitive findings may indicate that interventions affecting the sympathetic nervous system may exert complex effect on the tumor progression. Based on these data we may suggest that the potential therapeutic interventions affecting the sympathetic signaling in the tumor tissue and its microenvironment should attenuate the sympathetic neurotransmission not only temporarily but till the complete regression of the tumor tissue.

Dental pulp mesenchymal stem/stromal cells labeled with iron sucrose release exosomes and cells applied intra-nasally migrate to intracerebral glioblastoma.

We report on a simple iron oxide (Venofer) labeling procedure of dental pulp mesenchymal stem cells (DP-MSCs) and DP-MSCs transduced with yeast cytosinedeaminase::uracilphosphoribosyltransferase (yCD::UPRT-DP-MSCs). Venofer is a drug approved for intravenous application to treat iron deficiency anemia in patients. Venofer labeling did not affect DP-MSCs or yCD::UPRT-DP-MSCs viability and growth kinetics. Electron microscopy of labeled cells showed internalized Venofer nanoparticles in endosomes. MRI relativity measurement of Venofer labeled DP-MSCs in a phantom arrangement revealed that 100 cells per 0.1 ml were still detectable. DP-MSCs or yCD::UPRT-DP-MSCs and the corresponding Venofer labeled cells release exosomes into conditional medium (CM). CM from yCD::UPRT-DP-MSCs in the presence of a prodrug 5-fluorocytosine caused tumor cell death in a dose dependent manner. Iron labeled DP-MSCs or yCD::UPRT-DP-MSCs sustained their tumor tropism in vivo; intra-nasally applied cells migrated and specifically engrafted orthotopic glioblastoma xenografts in rats.

[Intestinal microbiota and the brain: multilevel interactions in health and disease]. / Os crevo-mozog: význam interakcií medzi crevnou mikrobiotou a mozgom za fyziologických a patologických situácii.

Commensal bacteria of the digestive tract are separated from the brain by multiple barriers. Despite that bacteria residing in the intestine and the neurons of the brain interact by neural and humoral pathways. Mental processes, such as the stress response, may affect the composition and function of intestinal bacteria via the brain-gut axis. On the other hand, intestinal bacteria can influence the processes in the brain through the gut-brain axis. Disruption of these interactions may be involved in various alterations both in the function of the gastrointestinal tract and the brain function.

Exaggerated activity of HPA axis in obese rats fed normocaloric liquid nutrition.

Experimental and clinical studies have shown alterations in activity of systems responsible for neuroendocrine stress response in obese individuals. Therefore we investigated the effect of palatable normocaloric liquid nutrition (Fresubin) on alterations in activity of the hypothalamic-pituitary-adrenal (HPA) axis in male Wistar rats of different developmental stages. Control rats (CON) received standard pellet chow all the time from weaning (21st day of age) to 150 days. Fresubin was administered throughout the experiment (LN), only in juvenility (from 21st to 90th day of age; LNJ) or only in adulthood (from 90th to 150th day of age; LNA). Body weight and energy intake were periodically monitored. Adrenal gland and fat tissue weight and plasma corticosterone levels (CORT) was determined after sacrification. Fresubin intake induced obesity in LN and LNA rats. In LN and LNA rats were observed elevated serum CORT levels, but only in LN rats with significant twofold increase compared to LNJ rats. However, the weight of adrenal glands did not differ between LN, LNJ and LNA experimental groups. Based on our results, we suggest, that obesity induced by Fresubin in LN and LNA rats is accompanied by increased HPA activity represented by elevated plasma CORT levels in these rats.

Deafferentation of the hypothalamic paraventricular nucleus (PVN) exaggerates the sympathoadrenal system activity in stressed rats.

OBJECTIVE: The hypothalamic paraventricular nucleus is a key structure in the regulation of the autonomic and neuroendocrine systems response to acute and chronic stress challenges. In this study, we examined the effect of a mechanical posterolateral deafferentation of the PVN on the activity of sympathoadrenal system (SAS) and hypothalamo-pituitary-adrenal (HPA) axis by measuring plasma concentrations of epinephrine (EPI), norepinephrine (NE), and corticosterone (CORT) in rats exposed to acute immobilization (IMO) stress. METHODS: The surgical posterolateral deafferentation of the PVN (PVN-deaf) was performed by Halasz knife, in brain of the adult male Sprague Dawley rats, according to coordinates of a stereotaxic atlas. Sham-operated (SHAM) animals underwent a craniotomy only. The animals were allowed to recover 14 days. Thereafter, the tail artery was cannulated and the animals exposed to acute IMO for 2 h. The blood samples were collected via cannula at the time points of 0, 5, 30, 60, and 120 min of the IMO. Concentrations of plasma EPI, NE, and CORT were determined by radioimmunoassay. RESULTS: The IMO-induced elevation of plasma EPI concentrations in the PVN-deaf rats reached statistical significance at 60 min of the IMO, when compared to SHAM rats. Similarly, the stress-induced elevation of the NE plasma levels in the PVN-deaf rats was significantly exaggerated at all time intervals of IMO in comparison with SHAM rats, whereas plasma CORT levels were significantly reduced. CONCLUSIONS: In contrast to the traditional view of excitatory role of the PVN in response to stress, our data indicate that some projections from the PVN to caudally localized hypothalamic structures, the brainstem or the spinal cord, exert inhibitory effect on the SAS system activity during acute IMO stress. The data indicate that stress-induced activation of the HPA axis is partially dependent on inputs from the brainstem to the PVN.

Daily profile of glut1 and glut4 expression in tissues inside and outside the blood-brain barrier in control and streptozotocin-treated rats.

Glucose is molecule usually studied in relation to metabolism. Except for this traditional view, it is known that under certain conditions glucose can serve as a signal molecule for the circadian system. The circadian system is entrained by relevant synchronizing cues that can be tissue-dependent. Central oscillator is synchronized mainly by light-dark cycle, while peripheral oscillators can be entrained by food intake. Glucose transport in the organism is controlled by insulin dependent and independent mechanism. Therefore, we employed streptozotocin-induced diabetes to elucidate the influence of metabolic changes on glucose transporter (glut1, glut4) 24-h expression profile in peripheral oscillators in tissues, inside (frontal cortex, cerebellum) and outside (heart) the blood-brain barrier. Diabetes was induced by streptozotocin injection. Seventeen days later, sampling was performed during a 24-h cycle. Gene expression was measured using real-time PCR. We observed down-regulation of glut1 and glut4 expression in the heart of diabetic rats. The expression of glut1 and glut4 in brain areas was not down-regulated, however, we observed trend to phase advance in glut1 expression in the cerebellum. These results may indicate higher glucose levels in diabetic brain, which might influence regulation of clock gene expression in different manner in brain compared to periphery.

Effect of streptozotocin-induced diabetes on clock gene expression in tissues inside and outside the blood-brain barrier in rat.

The circadian system allows organisms to remain synchronized with rhythmic environmental changes with a 24-h period. The molecular mechanism of circadian oscillations is based on the rhythmic expression of clock genes organized in feedback loops. Alterations in the circadian system contribute to the development of several pathological conditions including diabetes, but the exact mechanisms responsible for such alterations are not known. Therefore, we employed streptozotocin-induced diabetes to elucidate the influence of metabolic changes on clock gene (clock, npas2, per2) expression in peripheral oscillators in tissues inside (frontal cortex, cerebellum) and outside (heart, kidney) the blood-brain barrier. Diabetes was induced by streptozotocin injection. Seventeen days later, sampling was performed during a 24-h cycle. Gene expression was measured using real-time PCR. We observed a phase advance in rhythmic clock gene expression in the heart and kidney of diabetic rats. The study also focused on the possible role of npas2 in locomotor activity regulation in diabetic animals. The most pronounced changes were observed in the frontal cortex, which displayed up-regulation of npas2 expression. A change in locomotor activity was observed in diabetic rats during the dark phase of the 24-h cycle. We suggest that the altered function of the frontal cortex induced by diabetes might contribute to the modified behavior of diabetic rats.

Long-term liquid nutrition intake and development of obesity: differences between young and adult rats.

OBJECTIVE: Obesity is particularly associated with an increased consumption of palatable fat and sugar dense food and beverages. Therefore, we examined the effect of a normocaloric liquid diet (Fresubin) with increased carbohydrate content (constituting 55% of calories) on development of obesity in different developmental periods in male Wistar rats. METHODS: Fresubin was provided to 3 groups of rats: the first group received Fresubin immediately after weaning (21st day of age) to the end of experiment (150th day of age) for 5 months; the second group was fed with Fresubin from weaning to adulthood (90th day of age) for 3 months; and the third group received Fresubin only in adulthood (from 90th to 150th day of age) for 2 months. The control group was fed with standard pellet chow from weaning to the end of the experiment. Body weight, food and water intake were periodically measured. After terminating the experiment, the adiposity index was determined. RESULTS: Rats fed with liquid nutrition showed increased energy intake and body weight in comparison with the control rats. Interestingly, while obesity in the juvenile rats developed as late as of 13 weeks after the Fresubin intake, the adult rats fed with liquid nutrition had significantly elevated the body weight already 2 weeks after starting the treatment. Increased adiposity index was observed in both groups of rats fed with Fresubin during the whole study as well as the adulthood. CONCLUSIONS: Our data indicate that feeding of male Wistar rats with a high carbohydrate normocaloric diet results in a substantial development of obesity. Moreover, exposure of juvenile individuals to obesogenic environment leads, after a certain "latent period", to the development of obesity that may reflect low protein content of used liquid diet or higher resistance of juvenile organism to the obesogenic factors. Finally, based on the data obtained we suggest that Fresubin, with respect to its properties, may serve as a diet for the development of obesity which may exemplify an "obesity model" applicable in small laboratory animals.

Medial prefrontal cortex transection enhanced stress-induced activation of sympathoadrenal system in rats.

OBJECTIVE: The medial prefrontal cortex (mPFC) projects to the sympathetic premotor and preganglionic neurons. Besides the well described modulatory effect on the hypothalamo-pituitary-adrenal (HPA) axis activity, the mPFC also exerts modulatory effect on the activity of the sympathoadrenal system (SAS). The aim of the present study was to find out whether interruption of the anatomical interconnections between the mPFC neurons and hypothalamic, brainstem and spinal cord structures may affect the SAS and HPA axis activities determined by the plasma catecholamines (epinephrine, EPI and norepinephrine, NE) and corticosterone (CS) levels in the rats exposed to a single immobilization (IMO) stress. METHODS: The posterior transection of the mPFC was performed bilaterally by inserting a V-shaped blade into the brain of adult male Sprague Dawley rats. Sham-operated animals (controls) underwent a craniotomy only. The animals were allowed to recover for 14 days. Thereafter, the tail artery was cannulated and the animals exposed to acute IMO for 2 h. The blood samples were collected at 5, 30, 60, 120 min of the IMO. Concentrations of the plasma EPI, NE, and CS were determined by radioimmunoassay. RESULTS: The IMO-induced elevation of the plasma EPI levels in the mPFC-transected rats reached statistical significance at 120 min of the IMO, when compared to controls. Similarly, plasma NE levels were significantly increased at 60 and 120 min of the IMO in the mPFC-transected animals in comparison with controls. The transection had no significant effect on the plasma CS levels. CONCLUSION: The data indicate that the mPFC transection may enhance the IMO-induced SAS activity without affecting the activity of the HPA axis. We found that the mPFC may exert an inhibitory effect on the SAS activity in the stressed animals.

[The role of central nervous system in etiopathogenesis of peripheral organ diseases]. / Uloha centrálneho nervového systému v etiopatogenéze chorôb periférnych orgánov.

Current research on the etiopathogenesis of diseases of peripheral organs is primarily focused on the study of processes affecting those organs directly altered by diseases. As a result, therapeutic interventions are focused on the cells of those organs affected by pathological processes. However, pathological processes are not restricted to any "circumscribed" group of cells. Cells of tissue affected by pathological process interact with cells in the surrounding tissues. Moreover, pathologic processes also induce changes in the activity of the neuroendocrine and immune systems, which also affect the progression of pathological processes. The neurobiological view of diseases is based on the assumption that the nervous system processes signals related to pathological processes in peripheral organs and then consequently modulates it via the autonomic, neuroendocrine, and neuroimmune regulations. The aim of this paper is to explain the basis of the neurobiological view of diseases of the peripheral organs, and then discuss possible therapeutic consequences.

Chemical sympathectomy suppresses fibrosarcoma development and improves survival of tumor-bearing rats.

Both experimental and clinical data indicate that the sympathetic nervous system may affect the development of certain tumors. To test this, in the present study we combined in vivo and in vitro approaches to study the effect of the sympathetic nervous system on proliferation of BP6-TU2 fibrosarcoma cells. First, we investigated the effect of 6-hydroxydopamine-induced sympathectomy on tumor development and survival of tumor-bearing rats. One week after chemical sympathectomy, we injected the BP6-TU2 fibrosarcoma cells intraperitoneally into male Wistar rats. The sympathectomy significantly reduced the incidence of intraperitoneal tumors and resulted in significantly improved survival of tumor-bearing rats compared to those with intact sympathetic innervation. Using immunohistochemical methods, we found neuron-specific enolase immunopositive structures within fibrosarcoma tissue, indicating innervation of tumors. Finally, an in vitro study showed elevated proliferation of BP6-TU2 fibrosarcoma cells in response to adding norepinephrine to the culture medium. Our findings indicate that sympathetic nerves directly potentiate the proliferation of BP6-TU2 fibrosarcoma cells in rats.

Brain-liver interactions during liver ischemia reperfusion injury: a minireview.

KEYWORDS: The liver is a vital organ, with a wide range of functions. This organ plays an important role in the metabolism, including the glycogen storage, decomposition of red blood cells, plasma protein synthesis, hormone production, and detoxification. The liver is innervated by sympathetic and parasympathetic nerves which are involved in the regulation of the hepatic metabolism. Tissue injury connected with ischemia and reperfusion has been implicated in several clinical settings, including myocardial infarction, brain ischemia, and organ transplantation. Consequences of the liver ischemia reperfusion injury (LIRI) induce first of all an organ failure and afterwards multiorgan system damages that may eventually lead to a death. Many models with an attempt to reduce harmful consequences of the LIRI, directing to develop a variety of prophylactic strategies, has been introduced including models of warm, cold or normothermic ischemia, ischemic pre- and post-conditionings, pharmacological interventions, etc. In spite of the improvements in the medical care and accumulation of a large amount of experimental data concerning the prevention of ischemia and reperfusion related injuries, many destructive processes explanation still remains problematic.