Effects of cannabinoids in Parkinson's disease animal models: a systematic review and meta-analysis.

Objectives: Cannabis has been proposed as a potential treatment for Parkinson's disease (PD) due to its neuroprotective benefits. However, there has been no rigorous review of preclinical studies to evaluate any potential treatment effect. This systematic review was undertaken to provide evidence in support or against a treatment effect of cannabinoids in animal models of PD. Methods: Databases were searched for any controlled comparative studies that assessed the effects of any cannabinoid, cannabinoid-based treatment or endocannabinoid transport blocker on behavioural symptoms in PD animal models. Results: A total of 41 studies were identified to have met the criteria for this review. 14 of these studies were included in meta-analyses of rotarod, pole and open field tests. Meta-analysis of rotarod tests showed a weighted mean difference of 31.63 s for cannabinoid-treated group compared with control. Meta-analysis of pole tests also showed a positive treatment effect, evidenced by a weighted mean difference of -1.51 s for cannabinoid treat group compared with control. However, meta-analysis of open field test demonstrated a standardised mean difference of only 0.36 indicating no benefit. Conclusion: This review demonstrates cannabinoid treatment effects in alleviating motor symptoms of PD animal models and supports the conduct of clinical trials of cannabis in PD population. However, there is no guarantee of successful clinical translation of this outcome because of the many variables that might have affected the results, such as the prevalent unclear and high risk of bias, the different study methods, PD animal models and cannabinoids used.

Protection of cannabinoid to retinal ganglion cells against oxygen-glucose deprivation damage / 中华实验眼科杂志

Background Acute retinal ischemia anoxic injury is common in eye disorders,such as acute glaucoma,central retinal artery occlusion and ischemic optic neuropathy,etc.This will cause retinal ischemia anoxic injury and induce retinal ganglion cells (RGCs) death in addition.Endogenous cannabinoid (CB) and its receptors are involved in the central nervous system injury,ischemia,inflammation,and poisoning and other physiological and pathological process.Objective This study was to investigate the effect of CB on RGCs damage induced by oxygen-glucose deprivation (OGD).Methods The eyeballs were obtained from 6-week-old normal C57BL/6J mice to prepare retinal frozen sectionsand the expression and distribution of cannabinoid receptors (CB1R and CB2R) in RGCs was detected by immunofluorescence staining.The eyeballs of ten newborn C57BL/6J mice (postnatal 0-3 days) were obtained after immersed by 75％ alcohol and the retinas were isolated in preeooling DMEM for the primary culture of RGCs.The cells were identified by detecting the expression of Brn3a,a marker of RGCs,with immunofluorescence staining.Then the cells cultured for 14 days were divided into normal control group (in complete culture medium+95％ air+5％ CO2) and OGD group (in glucose-free medium+95％ N2 +4％ CO2 + 1％ O2) for 20 hours.The mitochondrial damage and RGCs morphology changed were evaluated by JC-1 staining to observe the mitochondrial membrane potential change.SR141716A (CB1R antagonist,1 μmol/L),SR144528 (CB2R antagonist,1 μmol/L) and 5 or 10 μmol/L WIN 55212-2 (CB1R and CB2R agonist) were added,and the survival rate of RGCs was assayed MTT.Results CBR was positively expressed in various layers of normal mouse retinas.The cells in the normal control group showed uniform size and polygon in shape with the long and thin axons,and the expression of Brn-3a was seen in the cells.However,in the OGD group,cell shrinkage and fragments were found and most of the axons disappeared.The expression of Brn-3a was evidently weakened.The fluorescence intensity of JC-1 was evidently weakened in the OGD group compared with the normal control group,showing the reduce of mitochondrial membrane potential.MTT assay showed that the survival rate of RGCs was (100.00± 13.87)％,which was significantly higher than (89.52-± 18.16)％ in the normal control group (q =8.065,P =0.008).The mean survival rates of RGCs were (116.63±22.21)％ and (112.61 ±19.02)％ in the cells treated by SR141716A and SR144528,and that in the normal cells was (89.52 ± 18.16)％ in the OGD group,with significant differences between SR141716A-or SR144528-treated cells and normal cells (q =29.780,17.391;both at P＜ 0.01).Conclusions Hypoxia and glucose-free up-regulate the expression of CB and activate CB pathway.Inhibition of activation CBR process has a neuroprotection effect under the Hypoxia and glucose-free condition.

Avaliação do papel do sistema canabidiol em um modelo de lesão renal por isquemia/reperfusão em animais / Evaluation of the role of the cannabidiol system in an animal model of ischemia/reperfusion kidney injury

RESUMO Objetivo: Investigar os efeitos da administração de canabidiol em um modelo de isquemia/reperfusão renal em animais. Métodos: Foi induzida uma lesão renal, por meio de 45 minutos de isquemia renal seguida por reperfusão. Administrou-se canabidiol (5mg/kg) imediatamente após a reperfusão. Resultados: A isquemia/reperfusão aumentou os níveis de interleucina 1 e fator de necrose tumoral, o que foi atenuado pelo tratamento com canabidiol. Além disso, o canabidiol foi capaz de diminuir o dano oxidativo de lipídios e proteínas, mas não os níveis de nitrito/nitrato. A lesão renal após isquemia/reperfusão pareceu ser independente da expressão dos receptores canabidiol-1 e canabidiol-2, já que não houve aumento significante desses receptores após a reperfusão. Conclusão: O tratamento com canabidiol teve um efeito protetor contra a inflamação e o dano oxidativo em um modelo de isquemia/reperfusão renal. Esses efeitos parecem não ocorrer via ativação dos receptores canabidiol-1/canabidiol-2.

ABSTRACT Objective: This work aimed to investigate the effects of the administration of cannabidiol in a kidney ischemia/reperfusion animal model. Methods: Kidney injury was induced by 45 minutes of renal ischemia followed by reperfusion. Cannabidiol (5mg/kg) was administered immediately after reperfusion. Results: Ischemia/reperfusion increased the IL-1 and TNF levels, and these levels were attenuated by cannabidiol treatment. Additionally, cannabidiol was able to decrease lipid and protein oxidative damage, but not the nitrite/nitrate levels. Kidney injury after ischemia/reperfusion seemed to be independent of the cannabidiol receptor 1 and cannabidiol receptor 2 (CB1 and CB2) expression levels, as there was no significant increase in these receptors after reperfusion. Conclusion: The cannabidiol treatment had a protective effect against inflammation and oxidative damage in the kidney ischemia/reperfusion model. These effects seemed to be independent of CB1/CB2 receptor activation.

Expression of cannabinoid receptor type 2 in skin lesions of psoriasis vulgaris / 中华皮肤科杂志

Objective To investigate the expression of cannabinoid receptor type 2 (CNR2) in skin lesions of psoriasis vulgaris,and to explore its significance.Methods Tissue samples were obtained from lesions and perilesional skin of 20 patients with psoriasis vulgaris,and normal skin of 10 human controls without psoriasis or other autoimmune dermatoses.Real-time fluorescence-based quantitative PCR and immunohistochemistry were performed to determine the mRNA and protein expression levels of CNR2 in these samples.Statistical analysis was carried out by using two-sample t test and chi-square test.Results CNR2 mRNA and protein were expressed in the normal control skin,lesional skin and perilesional skin tissues.As immunohistochemistry showed,CNR2 was distributed diffusedly in the prickle cell layer in lesional skin,but expressed in the basal cell layer of the epidermis in normal control skin and perilesional skin.The mRNA expression level (2-△△α) of CNR2 was significantly higher in lesional skin than in normal control skin and perilesional skin tissues (3.97 vs.1.00 and 1.49,both P ＜ 0.05),but similar between normal control skin and perilesional skin tissues (P ＞ 0.05).The expression rate of CNR2 protein was significantly higher in lesional skin (90％ (18/20) than in perilesional skin (15％ (3/20),x2 =22.56,P ＜ 0.01) and normal control skin tissues (10％ (2/20),c2 =18.37,P＜ 0.01),while there was no significant difference between normal control skin and perilesional skin tissues (x2 =0.14,P =0.70).Conclusions The mRNA and protein expressions of CNR2 are both increased in skin lesions of psoriasis vulgaris,suggesting that CNR2 may be related to the occurrence and development of psoriasis vulgaris.

Protective effects of cannabinoid receptor agonist WIN55,212-2 preconditioning on spinal cord ischemia reperfusion injury in rats / 中国医师杂志

Objective To explore the effects of cannabinoid receptor agonist WIN55,212-2 preconditioning on spinal cord ischemia reperfusion injury in rats.Methods A total of 32 male Sprague-Dawley rats was randomly divided into four groups (n =8):sham group,control group,dimethyl sulfoxide(DMSO) group which was given intraperitoneally DMSO 0.3 ml 30 min before ischemia reperfusion,and WIN group which was given intraperitoneally WIN55,212-2 1 mg/kg 30 min before ischemia reperfusion.Each rat was neurologically assessed at 24 h and 48 h after reperfusion by Tarlov scale,and the number of normal motor neurons at anterior horn of the spinal cord was recorded.Res uits The Tarlov scale of WIN group was significantly higher than that control and DMSO groups (P ＜ 0.05).There were more normal motor neurons at anterior horn of the spinal cord in WIN group than those in control and DMSO groups (P ＜ 0.05).Conclusions Cannabinoid receptor agonist WIN55,212-2 preconditioning might attenuate spinal cord ischemia reperfusion injury.

Sistema endocanabinoide y desarrollo de esteatosis hepática / A role for the endocannabinoid system in hepatic steatosis

The endocannabinoid system (SEC) is an important modulator of several metabolic functions. This system is composed by cannabinoid receptors type 1 and 2 (RCB1 and RCB2), their endogenous ligands, known as endocannabinoids, and the enzymes involved in their synthesis and degradation. A deregulated SEC originates metabolic alterations in several tissues, resulting in the typical manifestations of the metabolic syndrome. Liver steatosis of different origins constitutes a physiopathological condition where an altered hepatic SEC is observed. In this condition, there is an increased expression of RCB1 and/or higher endocannabinoid levels in different hepatic cells, which may exert an autocrine/paracrine hyperstimulation of RCB1/RCB2. Activation of RCB1 stimulate the expression of several hepatocyte lipogenic factors, thus leading to increased de novo fatty acids synthesis and consequently to an abnormal accumulation of triglycerides. The effect of RCB2 activity on hepatic function is still controversial because, on one side its stimulation has an interesting protective effect on alcoholic liver disease while, on the other, it may enhance the development of hepatic steatosis in experimental models of diet-induced obesity. In this review we discuss the proposed mechanisms by which SEC is involved in the etiology of hepatic steatosis, as well as the therapeutic possibilities involving peripheral RCB1/RCB2 antagonism/agonism, for the treatment of this condition.

Effect of curcumin on expression of cannabinoid receptor 1 and NR2B in spinal cord dorsal horn and dorsal root ganglion neurons in a rat model of neuropathic pain / 中华麻醉学杂志

Objective To investigate the effect of curcumin on the expression of cannabinoid receptor 1 (CBR1) and NR2B subunit-containing NMDA receptor in spinal cord dorsal horn and dorsal root ganglion (DRG) neurons in a rat model of neuropathic pain.Methods Seventy-two male Sprague-Dawley rats,weighing 200-230 g,were randomly divided into 4 groups ( n =18 each):sham operation group (S group),chronic constrictive injury (CCI) group,curcumin group (Cur group) and solvent control group (SC group).Neuropathic pain was induced by CCI.The sciatic nerve was exposed and 4 loose ligatures were placed on the sciatic nerve at 1 mm intervals in groups CCI,Cur and SC.Curcumin was injected intraperitoneally at 100 mg· kg- 1· d-1 for 14 consecutive days after operation in Cur group,while the equal volume of dimethyl sulfoxide was given instead of curcumin in SC group.Mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were measured on 2 days before operation and on 1,3,7,10 and 14 days after operation.Six rats in each group were sacrificed on 3,7 and 14 days after operation and the lumbar segments of the spinal cord ( L4,5 ) and DRGs were removed to determine the expression of CBR1 and NR2B by immuno-histochemistry.Results Compared with S group,MWT was significantly decreased,TWL was significantly shortened,and the expression of CBR1 and NR2B in spinal cord dorsal horn and DRG neurons was up-regulated after operation in the other three groups (P ＜ 0.05 ).Compared with CCI group,MWT was significantly increased,TWL was significantly prolonged,the expression of CBR1 inspinal cord dorsal horn and DRG neurons was up-regulated,and the expression of NR2B in spinal cord dorsal horn and DRG neurons was down-regulated after operation in group Cur (P ＜ 0.05 ),and no significant change in the parameters mentioned above was found in group SC ( P ＞ 0.05 ).Conclusion Curcumin can alleviate neuropathic pain in rats,and up-regulation of CBR1 expression and down-regulation of NR2B expression in spinal cord dorsal horn and DRG neurons are involved in the mechanism.

Effects of cannabinoid 1 receptor on regulation of visceral sensitivity in rats with acute restraint stress / 中华消化杂志

Objective To investigate the effects of cannabinoid 1 receptor (CB1R) on regulating visceral sensitivity in rats with acute partial restraint stress. Methods Thirty Sprague-Dawley rats were divided into blank control (sham stress), acute stress and CB1R groups with 10 each. The frequency of discharge of electromyogram (EMG) was recorded at the 1st, 2nd, 5th and 8th day to evaluate the visceral sensitivity to colorectal distension (CRD) in rats. The expression of the CB1R mRNA was determined by means of RT-PCR at day 8. Results There was no significant difference in baseline discharge frequency among three groups at the 1st day. But the discharge frequencies corresponding to CRD at 40,60,80 mm Hg at the 2nd day were significantly lower in CB1R group [(22.37±1.49)/min, (42.24±3.03)/min and (69.09±5.54)/min, respectively] than in acute stress group [(39.71±1.84)/min, (84.45±8.85)/min and (112.56±11.66)/min, respectively, P<0.05)]. The discharge frequencies corresponding to CRD at 40, 60,80 mm Hg in acute stress group [(104.12±6.77)/min, (158.07±18.68)/min, (193.58±25.69)/min,respectively] showed a significant elevation at the 5th day in comparison with blank control group[(36.33±5.42)/min, (74.07±8.25)/min, (102.94±7.95)/min, respectively, P<0.05] or CB1R group [(74.66±6.44)/min,(140.10±4.68)/min and (160.39±5.60)/min,respectively, P<0.05]. However, at the 8th day after stress, there was no significant difference in discharge frequency among three groups. The expressions of CB1R mRNA in ileocecal junction, proximal colonic and distal colonic tissues were significantly higher in acute stress group (2.53±0.52, 2.29±0.42, 2.54±0.29 respectively) than in blank control group(0.56±0.15, 0. 73±0.12, 0.82±0.09, respectively, P<0.05). There was no effect of CB1R agonist on CB1R mRNA expression in rats. Conclusion The visceral sensitivity in rats induced by stress can trigger the accommodation of endogenous cannabinoid system that plays an important role in modulation of visceral sensitivity.

Expression and significance of cannabinoid receptor 2 in malignant melanoma / 中华皮肤科杂志

Objective To investigate the expression of cannabinoid receptor 2 (CB2) in pigmented nevus and malignant melanoma and its significance. Methods The protein and mRNA expressions of CB2 were measured in tissue samples of 20 patients with pigmented nevus and 20 patients with malignant melanoma using immunohistochemical staining and RT-PCR, respectively. Results CB2 was expressed in both pigmented nevus and malignant melanoma. In tissue of pigmented nevus, CB2 was chiefly expressed in nevocytes and basal cell layer, and only a small quantity of CB2 was expressed in subcutaneous tissue. Statis-tical differences were observed between samples of malignant melanoma and pigmented nevus in the expres-sion intensity of CB2 (P < 0.05). Conclusions Increased protein and mRNA expressions of CB2 are observed in tissue of malignant melanoma, and the expression intensity of CB2 is higher in tissue of malig-nant melanoma than in that of pigmented nevus.

Neuroprotective effect of repeated WIN 55,212-2 preconditioning on focal cerebral ischemia-reperfusion injury in rats / 解放军医学杂志

Objective To explore the neuroprotective effect of repeated preconditioning with cannabinoid receptor agonist WIN 55,212-2 on focal cerebral ischemia-reperfusion injury in rats.Methods Focal cerebral ischemia was induced by middle cerebral artery occlusion(MCAO)for 120min.Fifty male SD rats were randomly assigned to five groups(10 each):rats in control group and dimethyl sulphoxide group(DMSO group)were intraperitoneally administered 0.3ml normal saline and 0.3ml DMSO once a day for 5 days.Rats in WIN 55,212-2 preconditioning groups(including WIN1,WIN3 and WIN5 group)received intraperitoneal injection of 1mg/kg WIN 55,212-2(dissolved with 0.3ml DMSO)once a day for 1d,3d and 5d,respectively.All animals underwent MCAO operation 24h after last pretreatment to reproduce temporal(120min)focal cerebral ischemia model.The neurological function score(NFS)was evaluated at 24,48 and 72h after reperfusion.Brain infarct was identified with 2% 2,3,5-triphenyltetrazolium chloride(TTC)staining 72h after reperfusion,and the brain infarct volume was expressed as percentage of normal cerebral hemisphere volume.Results The NFSs of rats in WIN 55,212-2 preconditioning groups(WIN1,WIN3 and WIN5 group)were significantly higher,and the infarct volumes were significantly smaller than that in control group and DMSO group at 24h,48h and 72h after reperfusion(P0.05).Conclusion The neuroprotective effect of repeated preconditioning with cannabinoid receptor agonist WIN 55,212-2 may be enhanced by increased time of pretreatment.