A phase I/II, open-label, randomised study of nintedanib plus mFOLFOX6 versus bevacizumab plus mFOLFOX6 in first-line metastatic colorectal cancer patients.

BACKGROUND: This randomised, open-label, phase I/II study evaluated the efficacy and safety of nintedanib, an oral, triple angiokinase inhibitor, combined with chemotherapy, relative to bevacizumab plus chemotherapy as first-line therapy in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Patients with histologically confirmed mCRC (adenocarcinoma), an Eastern Cooperative Oncology Group performance status ≤ 2 and adequate organ function were included. Patients were randomised 2:1 to receive nintedanib 150 mg or 200 mg b.i.d. plus mFOLFOX6 (oxaliplatin 85 mg/m(2), l-leucovorin 200 mg/m(2) or d,l-leucovorin 400 mg/m(2), 5-fluoruracil bolus 400 mg/m(2) followed by 2400 mg/m(2), every 2 weeks) or bevacizumab (5 mg/kg every 2 weeks) plus mFOLFOX6. During phase I, patients underwent a 3 + 3 dose-escalation schema to determine the maximum tolerated dose (MTD) of nintedanib in combination with mFOLFOX6. The primary end point was progression-free survival (PFS) rate at 9 months. Objective response (OR) was a secondary end point. RESULTS: The nintedanib recommended phase II dose was 200 mg b.i.d. plus mFOLFOX6 based on safety data from phase I (n = 12). Of 128 patients randomised in the phase II part, 126 received treatment (nintedanib plus mFOLFOX6, n = 85; bevacizumab plus mFOLFOX6, n = 41). PFS at 9 months was 62.1% with nintedanib and 70.2% with bevacizumab [difference: -8.1% (95% confidence interval -27.8 to 11.5)]. Confirmed ORs were recorded in 63.5% and 56.1% of patients in the nintedanib and bevacizumab groups, respectively. The incidence of adverse events (AEs) considered related to treatment was 98.8% with nintedanib and 97.6% with bevacizumab; the incidence of serious AEs was 37.6% with nintedanib and 53.7% with bevacizumab. The pharmacokinetics of nintedanib and the components of mFOLFOX6 were unaffected by their combination. CONCLUSIONS: Nintedanib in combination with mFOLFOX6 showed efficacy as first-line therapy in patients with mCRC with a manageable safety profile and further studies in this population are warranted.

Sorafenib in patients with Child-Pugh class A and B advanced hepatocellular carcinoma: a prospective feasibility analysis.

BACKGROUND: Sorafenib has shown survival benefits in patients with advanced hepatocellular carcinoma (HCC) and Child-Pugh (CP) class A liver function. There are few prospective data on sorafenib in patients with HCC and CP class B. PATIENTS AND METHODS: A consecutive prospective series of 300 patients with CP class A or B HCC were enrolled in a dual-phase trial to determine survival and safety data according to liver function (class A or B) in patients receiving oral sorafenib 800 mg daily. [Results of this study were presented in part at the ASCO 2012 Gastrointestinal Cancers Symposium, 19-21 January 2012. J Clin Oncol 2012; 30 (Suppl 4): abstract 306.] RESULTS: Overall progression-free survival (PFS), time to progression (TTP) and overall survival (OS) were 3.9, 4.1 and 9.1 months, respectively. For patients with CP class A versus B status, PFS was 4.3 versus 2.1 months, TTP was 4.2 versus 3.8 months and OS was 10.0 versus 3. 8 months. Extrahepatic spread was associated with worse outcomes but taken together with CP class, liver function played a greater role in reducing survival. Adverse events for the two CP groups were similar. CONCLUSION: Although patients with HCC and CP class B liver function have poorer outcomes than those with CP class A function, data suggest that patients with CP class B liver function can tolerate treatment and may still benefit from sorafenib.

[The surveillance of occupational risks. Problems and perspectives of the recent legislative framework after the national preliminary survey]. / I dati sanitari aggregati e di rischio dei lavoratori sottoposti a sorveglianza sanitaria. Risultati preliminari dello studio pilota nazionale sulle comunicazioni ex art. 40. D.lgs 81/2008.

BACKGROUND: Legislation in Italy concerning health, safety and prevention at the workplace recently established a new data communication standard OBJECTIVES: The findings are reported of a specific survey on 18 Local Health Units (ASL) over the entire Italian territory, aimed at identifying the critical points in data management and analyze the available information. METHODS: The occupational health physician for each company must collect and transmit information on the number of workers submitted to health surveillance protocols to the Local Health Unit. Information must be divided by risk factor and gender Local health Units then transmit the data to the Regions and finally to the Italian National Institute for Occupational Safety and Prevention (ISPESL). RESULTS: A sample of 22.977 companies was studied, providing information on about 410,009 workers undergoing health surveillance protocols. Carrying or moving heavy loads, exposure to noise, VDU and chemical substances were the most frequent risk factors. The difference between genders was significant in risk allocation, with exposures to VDU and biological agents prevalently among females. CONCLUSIONS: The information thus collected suffered from a lack of data organization and completeness in the sample under study, but nevertheless provides preliminary evidence of a map of occupational risks on a national basis, confirming the potential for the new law (D.Lgs 81/2008) to investigate health safety and prevention at the workplace.

Remote cell death in the cerebellar system.

Functional impairment after focal CNS lesion is highly dependent on damage that occurs in regions that are remote but functionally connected to the primary lesion site. This pattern is particularly evident in the cerebellar system, in which functional interactions between the cerebellar cortex, deep cerebellar nuclei, and precerebellar stations are of paramount importance. Diffuse degeneration after development of a focal CNS lesion has been associated with poor outcomes in several pathologies, such as stroke, multiple sclerosis, and brain trauma. A greater understanding of the mechanisms that underlie the spread of death signals from focal lesions, however, can aid in identifying a neuroprotective approach for CNS pathologies. To this end, studies on degenerative mechanisms in the inferior olive and pontine nuclei after focal cerebellar damage have been a valuable asset in which pharmacological approaches have been tested. In this review, we focus on mechanisms of remote cell death in cerebellar circuits, analyzing the neuroprotective effects of inflammation-modulating drugs in particular.

KIT and PDGFRalpha mutations in 104 patients with gastrointestinal stromal tumors (GISTs): a population-based study.

BACKGROUND: The prognostic significance of KIT or platelet-derived growth factor receptor alpha (PDGFRalpha) mutations in gastrointestinal stromal tumors (GISTs) is still controversial. PATIENTS AND METHODS: In all, 104 patients were diagnosed with GISTs by KIT immunoreactivity; tumor DNA was sequenced for the presence of mutations in KIT exons 9, 11, 13 and 17 and in PDGFRalpha exons 12 and 18. Disease-free survival (DFS) was analyzed in 85 radically resected patients. RESULTS: KIT mutations occurred in exon 11 (69), in exon 9 (11) and in exon 17 (1). PDGFRalpha mutations were detected in exon 18 (10) and in exon 12 (3). Ten GISTs were wild type. Exon 11 mutations were as follows: deletions in 42 cases and point mutations in 20 cases and insertions and duplications, respectively, in 2 and 5 cases. A better trend in DFS was evident for duplicated and point-mutated exon 11 KIT GISTs. There was a significant association between PDGFRalpha mutations, gastric location and lower mitotic index. Moreover, PDGFRalpha-mutated GISTs seemed to have a better outcome. CONCLUSIONS: Point mutations and duplications in KIT exon 11 are associated with a better clinical trend in DFS. PDGFRalpha-mutated GISTs are preferentially localized in the stomach and seem to have a favorable clinical behavior.

Cortical and subcortical distribution of ionotropic purinergic receptor subunit type 1 (P2X(1)R) immunoreactive neurons in the rat forebrain.

Ionotropic purinergic receptors (P2XR) are ATP-gated cationic channels composed of seven known subunits (P2X(1-7)R) and involved in different functions in neural tissue. Although their presence has been demonstrated in the brain, few studies have investigated their expression pattern. In particular, ionotropic purinergic receptor subunit type 1 (P2X(1)R) has been observed in the cerebellum and in brainstem nuclei. The present study investigates the P2X(1)R expression pattern in the rat forebrain using immunohistochemistry. The specificity of the immunolabeling has been verified by Western blotting and in situ hybridization methods. P2X(1)R immunoreactivity was specifically localized in neurons, dendrites and axons throughout the forebrain. Characteristic differences in the distribution of P2X(1)R were observed in different cortical areas. In prefrontal, cingulate and perirhinal cortices, very intense labeling was present in neuronal bodies. In frontal, parietal, temporal and occipital cortices, immunostaining was lighter and mainly found in dendrites and axons. The hippocampal formation was intensely labeled. Labeling was present almost exclusively in dendrites and axons and never in neuronal bodies. The diencephalon was devoid of P2X(1)R positive neurons or fibers except for the medial habenular nucleus, which showed very intense P2X(1)R immunostaining. Furthermore, two subcortical regions, namely, the nucleus centralis of the amygdala and the bed nucleus of the stria terminalis, showed intense P2X(1)R neuronal labeling. Present data indicate that P2X(1)R are prevalent in forebrain areas involved in the integration of cognitive, limbic and autonomic functions.

Minocycline attenuates microglial activation but fails to mitigate degeneration in inferior olive and pontine nuclei after focal cerebellar lesion.

Degenerative changes in areas remote from the primary lesion site have been linked to the clinical outcome of focal brain damage, and inflammatory mechanisms have been considered to play a key role in the pathogenesis of these remote cell death phenomena. Minocycline is a tetracycline derivative, therapeutically effective in various experimental models of central nervous system (CNS) injuries that include inflammatory and apoptotic mechanisms, although recent findings have yielded mixed results. In this study, we investigated the effectiveness of minocycline treatment in reducing remote cell death. Glial activation and neuronal loss in precerebellar stations following cerebellar lesion were investigated using immunohistochemistry and Western blot techniques. Our results show that minocycline was effective in reducing microglial activations in axotomized precerebellar nuclei, but failed to mitigate either astrocytic response or neuronal loss. This finding supports the role of minocycline in modulating inflammatory response after CNS lesion and suggests its ineffectiveness in influencing degenerative phenomena in areas remote from the primary lesion site.

Features and predictors of activity limitations and participation restriction 2 years after intensive rehabilitation following first-ever stroke.

BACKGROUND: Although stroke-related disability has been extensively studied, only few studies have investigated Participation restriction in chronic stroke survivors. AIM: To identify features and predictors of Activity limitation and Participation restriction in the chronic phase of a first-ever stroke. DESIGN: Cross-sectional observational study. SETTING: Comprehensive stroke unit with outpatient rehabilitation facility. POPULATION: Subjects submitted to intensive rehabilitation after first-ever stroke, from 1st January 2009 to 31st December 2010. METHODS: Participation was investigated through the Frenchay Activity Index (FAI) and the Functional Status Questionnaire (FSQ) at 2.4±0.5 years after the event. Basic activities of daily living (ADL) and mood were also assessed through the Modified Barthel Index (MBI) and the Beck Depression Inventory (BDI). A retrospective search of the medical records looked for: type/side of brain lesion, stroke clinical syndromes, comorbidities and functional condition at discharge from intensive rehabilitation (upper limb motricity index-ULMI-, Functional Ambulation Category-FAC, MBI, cognitive deficits). RESULTS: Forty-five subjects (17 female, age 70.1±11.5 years) were enrolled. They showed a striking restriction in their Participation, mainly for FAI-outdoor activities (median FAI score was <50% of the theoretical maximum). A poor gait function (FAC) and an impaired mood (BDI) were the only independent predictors of FAI indoor (F=6.1; p=,005; R^2= 64%) and outdoor activities (F=4.1; P=0.01; R^2=48%), respectively. The univariate analysis showed a strong dependence of all FSQ scores from global disability (MBI), motor function impairment (ULMI and FAC) and cognitive deficits. Depression influenced "psychological function" score, whereas gait capacity was the only factor significantly associated with the "work performance" score. The gait function level, achieved after intensive rehabilitation, was extrapolated by the multivariate analysis, as the most powerful independent predictor of the chronic activity limitations, as measured by MBI (F=33.8, P<0.0001, R2=0.539). CONCLUSION: Gait dysfunction is the main factor of Activity limitations and Participation restriction in chronic stroke. Participation is restricted by global disability, depression, older age and dementia. More than 50% variance of Participation measures cannot be explained by the quoted factors. CLINICAL REHABILITATION IMPACT: The study results support the need to integrate the standard rehabilitation approach with vocational rehabilitation in order to reduce Participation restriction.

Intermediate lukewarm (20 degrees c) antegrade intermittent blood cardioplegia compared with cold and warm blood cardioplegia.

BACKGROUND: In the field of intermittent antegrade blood cardioplegia, 3 levels of temperature are commonly used: (1) cold (8 degrees C); (2) tepid (29 degrees C); and (3) warm (37 degrees C). Given the 21 degrees C spread and the metabolic changes that can occur between cold (8 degrees C) and tepid (29 degrees C) cardioplegia, we thought it worthwhile to test a temperature halfway between the cold and tepid levels. The aim of this study was to test the quality of myocardial protection provided by intermediate lukewarm (20 degrees C) cardioplegia by comparing it with cold and warm cardioplegia. Protection was assessed by measuring cardiac troponin I release. METHODS: One hundred thirty-five patients undergoing coronary artery bypass grafting were enrolled in a prospective randomized trial comparing cold (8 degrees C), intermediate lukewarm (20 degrees C), and warm (37 degrees C) antegrade intermittent blood cardioplegia. Cardiac troponin I concentrations were measured in serial venous blood samples. RESULTS: The total amount of cardiac troponin I released was significantly higher in the cold group (4.7 +/- 2.3 microg) than in the intermediate lukewarm (3.4 +/- 2.0 microg) or the warm (3.1 +/- 2.7 microg) groups. The cardiac troponin I concentration was significantly higher at hour 6 in the intermediate lukewarm group (1. 23 +/- 0.55 microg/L) than in the warm group (0.89 +/- 0.50 microg/L). CONCLUSIONS: Intermittent antegrade intermediate lukewarm blood cardioplegia is appropriate and clinically safe. Cardiac troponin I release suggests that intermediate lukewarm cardioplegia is better than cold cardioplegia but less effective than warm cardioplegia in low-risk patients. We therefore recommend the use of warm cardioplegia in low-risk patients.

Warm reperfusion and myocardial protection.

BACKGROUND: The aim of this study was to determine whether warm reperfusion improves myocardial protection with cardiac troponin I as the criteria for evaluating the adequacy of myocardial protection. METHODS: One hundred five patients undergoing first-time elective coronary bypass surgery were randomized to one of three cardioplegic strategies of either (1) cold crystalloid cardioplegia followed by warm reperfusion, (2) cold blood cardioplegia followed by warm reperfusion, or (3) cold blood cardioplegia with no reperfusion. RESULTS: The total amount of cardiac troponin I released tended to be higher in the cold blood cardioplegia with no reperfusion group (3.9+/-5.7 microg) than in the cold blood cardioplegia followed by warm reperfusion group (2.8+/-2.7 microg) or the cold crystalloid cardioplegia followed by warm reperfusion group (2.8+/-2.2 microg), but not significantly so. Cardiac troponin I concentration did not differ for any sample in any of the three groups. CONCLUSIONS: Our study showed that the addition of warm reperfusion to cold blood cardioplegia offers no advantage in a low-risk patient group.

Prevalence of mefE, erm and tet(M) genes in Streptococcus pneumoniae strains from Central Italy.

One hundred and seventy-three Streptococcus pneumoniae strains isolated from surveillance studies conducted in daycare centres were studied. The mefE, erm and tet(M) genes were detected in 16.2, 45.1 and 47.4% of isolates respectively. Agreement between PCR results and antibiotic susceptibility patterns was 100%. Macrolide resistance was due to the presence of erm in 73.6% of strains and to the presence of mefE in the remaining 26.4%. All tetracycline resistant strains carried the tet(M) gene. erm was associated with tet(M) in 98.7% of strains, whereas no isolate carrying mefE carried tet(M). A significant association was found between mefE and serogroup 6 (P < 0.0005) and between erm and tet(M) and serogroup 19 (P < 0.00001).

The clinical impact of FEM regimen (5-fluorouracil, 4-epidoxorubicin and mitomycin-C) in advanced gastric cancer patients.

The activity of FEM regimen in metastatic gastric cancer patients was assessed in seventy-seven patients receiving, as palliative treatment, 5FU 600 mg/m2 i.v. on days 1, 8, 29, 36; epiADR 70 mg/m2 i.v. on days 1, 29; MIT-C 10 mg/m2 i.v. on days 1, 29. Cycles were repeated every 58 days. One patient achieved a complete response and 12 a partial response, resulting in an overall response rate of 16% (95% CI: 8% to 24%). Median remission duration was 6 months. Median survival time for all patients was 8 months. Side-effects were mild and principally in the form of leukopenia (three episodes grade III). Our results support the recent findings about the lack of effectiveness of this regimen. Although it is a safe and well tolerable chemotherapeutic combination, FEM regimen should not be recommended as routinary treatment for gastric cancer patients who are not eligible for clinical trials.

Synchronous primary hepatic lymphoma and epidermoid lung carcinoma treated with chemotherapy and surgery.

While involvement of the liver by non-Hodgkin's lymphoma is a relatively frequent event, primary liver lymphoma is an uncommon disease. We describe a case of synchronous primary hepatic lymphoma and epidermoid lung carcinoma occurring in a 61-year-old male patient. Complete remission of both diseases was achieved with a radical approach, which included combination chemotherapy and surgery. The patient has now been in persisting complete remission for 40 months after surgery.

Mucocele-like tumour of the breast.

Mucocele-like (ML) lesions of the breast are rare tumours and were reported as benign lesions that histologically resembled colloid carcinoma of the breast when first described about sixteen years ago. Only subsequent reports identified ML lesions associated with ductal hyperplasia or carcinoma. The Authors report an additional case of ML tumour of the breast and review the available medical literature. A young asymptomatic woman, without family history of breast cancer, presented with a palpable breast mass. As the radiological aspect was not typical of a simple cyst, the patient underwent a fine needle aspiration biopsy which showed a doubtful pathological pattern compatible with fibroadenoma. The patient underwent surgery and the gross examination of the surgically removed mass revealed multiple aggregated cysts containing mucinous material. Microscopic examination showed a ML tumour of the breast, with aspects of cribriform ductal hyperplasia.

Inability of poly-ADP-ribosylation inhibitors to protect peripheral blood lymphocytes from the toxic effects of ADA inhibition.

We have evaluated the effectiveness of two inhibitors of poly-ADP-ribosylation, nicotinamide and 3-aminobenzamide as rescue agents in resting and PHA-stimulated lymphocytes damaged by the combination of deoxycoformycin (dCF) plus deoxyadenosine (dAdo). Incubation with dCF (10(-5)M) and dAdo (10(-4)M) for 18 hours, inhibited protein and RNA synthesis in unstimulated lymphocytes and impaired the ability of the cells to respond to PHA stimulation or to give rise to T-cell colonies in methyl-cellulose. Predominantly dead cells using trypan blue exclusion were observed at day 4, in both unstimulated and PHA-stimulated lymphocytes, whether or not the drugs were removed at 18 hours. The number of viable cells at day 4 increased from 13.7% to 41.1% with the addition of 5 mM nicotinamide, and to 28.8% with 5 mM 3-aminobenzamide added with dCF and dAdo. Although nicotinamide was able to prevent a fall in NAD concentration for 24h (but not for 48h) and to reduce the fall of cell ATP concentration, the inhibition by dCF and dAdo of protein synthesis, RNA synthesis, ability of cells to form colonies or to respond to PHA was not reversed. We conclude that inhibition of NAD utilisation by inhibiting ADP-ribosylation with nicotinamide or 3-aminobenzamide does not protect cells in vitro from deoxyadenosine toxicity with ADA inhibition and is not likely to give significant clinical benefit in ADA deficiency.

[Health promotion in the occupational setting: what are the prospects in the Italian situation?]. / La promozione della salute in ambiente di lavoro: quali prospettive nella situazione italiana?

Over the past decades advances in sciences and medicine have improved living and health conditions and lengthened life expectancy. These benefits are associated with an increase in prevalence of chronic degenerative diseases. With their multi-factorial aetiology these diseases are influenced by life styles and personal habits and require prolonged medical care and high social costs. Now days health is no longer considered as the absence of disease but a state of mental, physical and social well-being. The World Health Organization has defined health promotion as "the process of enabling people to increase control over and to improve health". Since the 70s in the USA many health promotion programmes have been proposed, especially by large corporations, in order to ensure a more efficient, productive and motivated work-force, to reduce health insurance costs and to provide a better company image. Workplaces,--particularly when the working population is relatively stable--are excellent areas for health promotion programmes because workers can be monitored over a long period of time. The most successful programmes are aimed at modifying behaviour in risk patterns (smoking, alcohol abuse, eating disorders, etc.) through information, active participation, screening, follow-up, personalized programmes, changes in the working environment, physical exercise programmes. These health promotion programmes are extremely hard to develop for Italian workers. Most firms are small or very small and much still remains to be done to eliminate well-known occupational risk factors. The current flexibility of modern work patterns could constitute a further obstacle.

Cannabinoid CB2 receptor (CB2R) stimulation delays rubrospinal mitochondrial-dependent degeneration and improves functional recovery after spinal cord hemisection by ERK1/2 inactivation.

Spinal cord injury (SCI) is a devastating condition of CNS that often results in severe functional impairments for which there are no restorative therapies. As in other CNS injuries, in addition to the effects that are related to the primary site of damage, these impairments are caused by degeneration of distal regions that are connected functionally to the primary lesion site. Modulation of the endocannabinoid system (ECS) counteracts this neurodegeneration, and pharmacological modulation of type-2 cannabinoid receptor (CB2R) is a promising therapeutic target for several CNS pathologies, including SCI. This study examined the effects of CB2R modulation on the fate of axotomized rubrospinal neurons (RSNs) and functional recovery in a model of spinal cord dorsal hemisection (SCH) at the cervical level in rats. SCH induced CB2R expression, severe atrophy, and cell death in contralateral RSNs. Furthermore, SCH affected molecular changes in the apoptotic cascade in RSNs - increased cytochrome c release, apoptosome formation, and caspase-3 activity. CB2R stimulation by its selective agonist JWH-015 significantly increased the bcl-2/bax ratio, reduced cytochrome c release, delayed atrophy and degeneration, and improved spontaneous functional recovery through ERK1/2 inactivation. These findings implicate the ECS, particularly CB2R, as part of the endogenous neuroprotective response that is triggered after SCI. Thus, CB2R modulation might represent a promising therapeutic target that lacks psychotropic effects and can be used to exploit ECS-based approaches to counteract neuronal degeneration.

Acute focal brain damage alters mitochondrial dynamics and autophagy in axotomized neurons.

Mitochondria are key organelles for the maintenance of life and death of the cell, and their morphology is controlled by continual and balanced fission and fusion dynamics. A balance between these events is mandatory for normal mitochondrial and neuronal function, and emerging evidence indicates that mitochondria undergo extensive fission at an early stage during programmed cell death in several neurodegenerative diseases. A pathway for selective degradation of damaged mitochondria by autophagy, known as mitophagy, has been described, and is of particular importance to sustain neuronal viability. In the present work, we analyzed the effect of autophagy stimulation on mitochondrial function and dynamics in a model of remote degeneration after focal cerebellar lesion. We provided evidence that lesion of a cerebellar hemisphere causes mitochondria depolarization in axotomized precerebellar neurons associated with PTEN-induced putative kinase 1 accumulation and Parkin translocation to mitochondria, block of mitochondrial fusion by Mfn1 degradation, increase of calcineurin activity and dynamin-related protein 1 translocation to mitochondria, and consequent mitochondrial fission. Here we suggest that the observed neuroprotective effect of rapamycin is the result of a dual role: (1) stimulation of autophagy leading to damaged mitochondria removal and (2) enhancement of mitochondria fission to allow their elimination by mitophagy. The involvement of mitochondrial dynamics and mitophagy in brain injury, especially in the context of remote degeneration after acute focal brain damage, has not yet been investigated, and these findings may offer new target for therapeutic intervention to improve functional outcomes following acute brain damage.

Distinct regulation of nNOS and iNOS by CB2 receptor in remote delayed neurodegeneration.

Hemicerebellectomy results in remote delayed degeneration of precerebellar neurons. We have reported that such a lesion induces type 2 cannabinoid receptor (CB(2)) expression in precerebellar neurons and that stimulation of CB(2), but not CB(1), has neuroprotective effects. In this study, we found that in the same model, the CB(2) agonist JWH-015 enhances neuronal nitric oxide synthase (nNOS) expression in axotomized neurons and that CB(2)-mediated neuroprotection is abrogated by pharmacological inhibition of nNOS. JWH-015 prevented the axotomy-induced upregulation of inducible NOS (iNOS) in astrocytes but had no effect on endothelial NOS (eNOS). In addition, we observed that JWH-015 significantly reduces hemicerebellectomy-induced neuroinflammatory responses and oxidative/nitrative stress. With regard to the signaling pathways of CB(2)/nNOS-mediated neuroprotection, we noted nNOS-dependent modulation of the expression of anti-oxidative (Hsp70) and anti-apoptotic (Bcl-2) proteins. These findings shed light on the interactions between the endocannabinoid and nitrergic systems after focal brain injury, implicating distinct functions of nNOS activation and iNOS inhibition in CB(2) signaling, which protect neurons from axotomy-induced cell death.

The endocannabinoid system: a new entry in remote cell death mechanisms.

Functional impairment after development of focal CNS lesions depends highly on damage that occurs in regions that are remote but functionally connected to the primary lesion site. These remote effects include cell death and structural changes, and they are important predictors of outcome in several pathologies, such as stroke, multiple sclerosis, and brain trauma. A greater understanding of the neuropathological mechanisms that exist in regions that are remote from focal primary lesions is therefore essential for the development of neuroprotective strategies. Endocannabinoids constitute a novel class of lipids that regulate mammalian cell apoptosis and the pathogenesis of neuroinflammatory and neurodegenerative diseases. In addition to well-described pharmacological actions in the brain, such as analgesia, hypokinesia, and hypothermia, endocannabinoids have been recently reported to control neuronal cell fate in various neuropathological conditions. Following brain injury, endocannabinoids are released, causing both protective and degenerative effects. Several hypotheses have been proposed to explain their role, but the mechanisms by which they act are largely unknown. New evidence indicates that the endocannabinoid system is a key participant in the determination of cell fate in remote cell death and its associated mechanisms. This review addresses recent findings on endocannabinoid function, focusing particularly on the relationships between the nitrergic, purinergic, and endocannabinoid systems.