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Representative brain slices (100 microns thick) stained with TTC at 48 hours post stroke onset. Normal tissue stains purple-red and infracted tissue appears white. a. Stroke saline b. Stroke leptin 1mg/kg c. Stroke leptin 4mg/kg d. Stroke leptin 8mg/kg. Please note that infarct size is smaller in animals treated with 1mg/kg of leptin compared with saline.
Source publication
Brain ischemia is associated with detrimental changes in energy production and utilization. Therefore, we hypothesized that leptin, an adipokynin hormone protecting against severe energy depletion, would reduce infarct volume and improve functional outcome after stroke. Male Sabra mice underwent permanent middle cerebral artery occlusion (PMCAO) by...
Contexts in source publication
Context 1
... volume significantly decreased following treatment with 1mg/kg of leptin 30 minutes after stroke induction ( Fig. 2A; p<0.05), but was not affected by either 4mg/kg or 8mg/kg (Fig. 3). As in the case of NSS, we wished to determine the therapeutic time window of the effects of leptin on infarct volume. Maximal protective effect was attained when leptin was administered after 30 minutes ( Fig. 2B; ANOVA: F (3,22) =5.462; planned comparisons: p<0.05 vs. vehicle), while administration of leptin 3h and 6h after did not ...
Context 2
... that exogenous leptin ameliorates motor disability and reduces infarct size. However, unlike Zhang et al., (2007) [14] who showed that 1mg/kg of leptin had no effect on infarct size while higher doses reduced it dosedependently, we were able to reduce infarct size using only 1mg/kg of leptin, while higher doses (4mg/kg and 8mg/kg) had no effect (Figs. 2A, 3). The effect of 1mg/kg of leptin versus the lack of effect of 4mg/kg was also evident on the examination of motor disability (Fig. 1A), and the expression of all genes tested in the cortex, except for CB 1 receptor (Figs. 4-9). The reason for this may be the use of different stroke models applied in different strains of miceSabra in our ...
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Citations
... Moreover, the heart expresses leptin receptors, synthesizes, and releases leptin into the coronary effluent, thus raising the possibility that the leptin of cardiac origin feeds back on cardiomyocytes to exert physiological effects [15]. Acute leptin administration has been shown to attenuate ischemic injury after stroke via the induction of anti-apoptotic pathways [16,17]. Myocardial protection induced by the leptin administered during reperfusion in the isolated heart protocol is mediated through a mechanism involving JAK/STAT signaling pathway activation coupled with mitochondrial permeability transition pore inhibition [18]. ...
Background: Leptin is an obesity-associated adipokine that has been implicated in cardiac protection against ischemia-reperfusion injury (IRI). In this study, concentration-dependent effects of leptin on myocardial IRI were investigated in the isolated rat heart. In addition, we analyzed myocardial miRNAs expression in order to investigate their potential involvement in leptin-mediated cardioprotection. Methods: The effect of leptin on IRI was examined in Langendorff-perfused rat hearts preconditioned with two leptin concentrations (1.0 nM and 3.1 nM) for 60 min. The hearts were subjected to 30 min global ischemia and 120 min reperfusion with buffer containing leptin in the respective concentration. Heart function and arrhythmia incidence were analyzed. Infarct size was assessed histochemically. Expression of miRNA-144, -208a, -378, and -499 was analyzed in the ventricular myocardium using RT-PCR. Results: The addition of 1.0 nM leptin to the buffer exerted an infarct-limiting effect, preserved post-ischemic ventricular function, and prevented reperfusion arrhythmia compared to 3.1 nM leptin. Myocardial expression of miRNA-208a was decreased after heart exposure to 1.0 nM leptin and significantly elevated in the hearts perfused with leptin at 3.1 nM. Conclusion: Acute administration of leptin at low dose (1.0 nM) results in cardiac protection against IRI. This effect is associated with reduced myocardial expression of miRNA-208a.
... Well documented pharmacological evidence supports functional crosstalk between the endocannabinoid system (ECS) and the endovanilloid system (EVS) (Di Marzo et al., 2002;Lastres-Becker et al., 2003;Morgese et al., 2007;Avraham et al., 2010;Chávez et al., 2010;Adamczyk et al., 2012;Arnold et al., 2012;Lowin and Straub, 2015;Rossi et al., 2015;Malek and Starowicz, 2016;Assimakopoulou et al., 2017;Bellini et al., 2017;Zhang et al., 2017;Punzo et al., 2018;Bhatta et al., 2019;Wi et al., 2020). Thus, these latest advances provide opportunities to develop innovative strategies for fighting disorders where biological targets of both systems are involved. ...
Both metabotropic (CBRs) and ionotropic cannabinoid receptors (ICRs) have implications in a range of neurological disorders. The metabotropic canonical CBRs CB1 and CB2 are highly implicated in these pathological events. However, selective targeting at CB2 versus CB1 offers optimized pharmacology due to the absence of psychoactive outcomes. The ICR transient receptor potential vanilloid type 1 (TRPV1) has also been reported to play a role in CNS disorders. Thus, activation of both targets, CB2 and TRPV1, offers a promising polypharmacological strategy for the treatment of neurological events including analgesia and neuroprotection. This brief research report aims to identify chemotypes with a potential dual CB2/TRPV1 profile. For this purpose, we have rationalized key structural features for activation and performed virtual screening at both targets using curated chemical libraries.
... α,β-Amyrin (a plant-derived pentacyclic triterpene) administered at 30 mg/kg, significantly decreased neuropathic hyperalgesia and persistent inflammation in the Swiss mouse model by activating CB2 and inhibiting the expressions of NF-kB, COX-2, and CREB (da Silva et al., 2011). Leptin (at 1 mg/kg i.p.) increased CB2 expression, prevented neurological deficits, and attenuated infarct volumes in male Sabra mice with photothrombosis-induced stroke (Avraham et al., 2010). ...
Defective proteostasis is associated with the gradual accumulations of misfolded proteins and is a hallmark of many age-associated neurodegenerative diseases. In the aged brain, maintenance of the proteostasis network presents a substantial challenge, and its loss contributes to the onset and progression of neurological diseases associated with cognitive decline due to the generation of toxic protein aggregates, a process termed 'proteinopathy'. Emerging evidence suggests that reversing proteinopathies by boosting proteostasis might provide an effective means of preventing neurodegeneration. From this perspective, phytochemicals may play significant roles as potent modulators of the proteostasis network, as previous reports have suggested they can interact with various network components to modify pathologies and confer neuroprotection. This review focuses on some potent phytochemicals that directly or indirectly modulate the proteostasis network and on their possible molecular targets. In addition, we propose strategies for the natural product-based modulation of proteostasis machinery that target proteinopathies.
... At the same time, another suggested that leptin might be used to attenuate ischemic injury after stroke via the induction of an anti-apoptotic state. 30 One study also suggested that leptin's benefit after stroke was related to its new neuroprotective role. 31 Furthermore, the role of leptin in glycaemic control had been suggested, 32 and the prognostic value of glucose serum level on admission in stroke patients treated with thrombolysis had been proposed. ...
Background
Leptin, an adipokine, has effects on the cardiovascular system with both protective and harmful role. This study aimed to assess the relationship between leptin and 3-month prognosis in ischemic stroke patients with type 2 diabetes.
Patients and Methods
As a prospective single-center observational study, we collected consecutive first-ever acute ischemia stroke with type 2 diabetes mellitus from February 2019 to February 2020. Serum samples were obtained at admission, and leptin serum levels were tested by the ELISA method. Logistic regression models were used to assess leptin’s prognostic value to predict the functional outcome and mortality within three months.
Results
Finally, two hundred and eleven patients were included, and the mean leptin serum level was 16.8 (SD. 6.9) ng/mL. At admission, 53.6% of those included patients (N=113) were defined as severe stroke (NIH Stroke Scale [NIHSS]>5). In multivariable models adjusted for other factors, leptin levels<11.6ng/mL (lowest quartile, Q1) related to severe stroke and the risk increased 175% (odds ratios [OR] =2.75; 95% confidence interval [CI]=2.13–3.38; P=0.002). Serum leptin levels on admission in patients with poor outcomes and nonsurvivors were significantly reduced (P<0.001 and P<0.001). Leptin levels <11.6ng/mL (lowest quartile, Q1) related to a higher risk of poor functional impairment (OR=5.13; 95% CI =3.25–6.86; P<0.001) and mortality (OR=3.19; 95% CI =2.03–4.25; P<0.001).
Conclusion
The data shows that leptin serum level is a useful prognostic biomarker in ischemic stroke patients with type 2 diabetes, and this relationship is negative.
... Noteworthy, comorbid conditions, such obesity, may exacerbate per se BBB dysfunction after stroke [49][50][51][52]. Available studies showed that several adipokines, including adiponectin, resistin and leptin, may cross BBB and act on the brain directly by influencing synaptic plasticity and microglia activation [53][54][55][56]. However, it is not yet clear if adipokines long released by visceral and perivascular adipose tissue because of obesity may be involved in the mechanisms of neuroplasticity and brain reorganization boosted by neurorehabilitation. ...
... Moreover, both cohorts of subjects enrolled in this study took a preventive therapy to lower obesity-related risk factors for cardiovascular disease, including the development of inflammatory responses. Therefore, the overexpressed levels of proinflammatory circulating adipokines, which are leptin and resistin, associated to a less bioavailability of anti-inflammatory adiponectin that we observed before neurorehabilitation in obese sub-acute stroke patients, when compared with adipokine values of obese subjects without stroke, could be consequent to the cascade of events induced by brain ischemic injury and could be sustained by the molecular mechanisms induced by activated microglia and astrocytes during stroke sub-acute phase [44,[53][54][55][56]. Interestingly, the modulation of adipokine gene transcription and the subsequent modified bioavailabity of adipokines are configured as adaptative responses evoked by cerebral ischemia to facilitate neuronal plasticity [59][60][61][62][63][64][65][66][67][68]. ...
Background
Limited studies concern the influence of obesity-induced dysregulation of adipokines in functional recovery after stroke neurorehabilitation.
Objective
To investigate the relationship between serum leptin, resistin, and adiponectin and functional recovery before and after neurorehabilitation of obese stroke patients. The adipokine potential significance as prognostic markers of rehabilitation outcomes was also verified.
Methods
Twenty obese post-acute stroke patients before and after neurorehabilitation and thirteen obese volunteers without-stroke, as controls, were examined. Adipokines were determined by commercially available enzyme–linked immunosorbent assay (ELISA) kits. Functional deficits were assessed before and after neurorehabilitation with the Barthel Index (BI), modified Rankin Scale (mRS), and Functional Independence Measure (FIM).
Results
Compared to controls, higher leptin and resistin values and lower adiponectin values were observed in stroke patients before neurorehabilitation and no correlations were found between adipokines and clinical outcome measures. Neurorehabilitation was associated with improved scores of BI, mRS, and FIM. After neurorehabilitation, decreased values of Body Mass Index (BMI) and resistin together increased adiponectin were detected in stroke patients, while leptin decreased but not statistically. Comparing adipokine values assessed before neurorehabilitation with the outcome measures after neurorehabilitation, correlations were observed for leptin with BI-score, mRS-score, and FIM-score. No other adipokine levels nor BMI assessed before neurorehabilitation correlated with the clinical measures after neurorehabilitation. The forward stepwise regression analysis identified leptin as prognostic factor for BI, mRS, and FIM.
Conclusions
Our data show the effectiveness of neurorehabilitation in modulating adipokines levels and suggest that leptin could assume the significance of biomarker of functional recovery.
... Previous studies indicated that leptin played an important role in regulating body intake and energy metabolism. Leptin also had other functions, such as causing oxidative stress [15] , promoting inflammatory response [16] , and inducing vascular endothelial cell apoptosis [17] , which were closely related to the occurrence, development, and clinical prognosis of cardiovascular disease and diabetes [18,19] . Ryan et al. [20] found that leptin could lead to vascular dysfunction by directly acting on LEPR. ...
Baclground The present study aimed to investigate whether N- acetylcysteine (NAC) protects human umbilical vein endothelial cells (HUVECs) against high glucose (HG)-induced injury by inhibiting leptin/leptin receptor (LEPR).
Methods HUVECs were treated with 40 mmol/L glucose for 24 h to establish a model of HG-induced endothelial cell injury; The cell viability was examined by cell counter kit-8(CCK-8) assay; The expression levels of leptin, LEPR, cleaved caspase-3 and endothelial nitric oxide synthase (eNOS) were detected by western blot. The intracellular levels of reactive oxygen species (ROS) were tested by DCFH-DA staining followed by photofluorography. Tumor necrosis factor-α (TNF-α)、nuclear factor-kappa B (NF-κB) and intercellular adhesion molecule-1 (ICAM-1) were detected by enzyme-linked immunosorbent assay (ELISA). The number of apoptotic cells was observed by photofluorograph with Hoechst 33258 nuclear staining. Mitochondrial membrane potential (MMP) was obtained using JC-1.
Results The expression of leptin and LEPR began to significantly increase after exposure to 40 mmol/L HG for 24 h. Pretreatment of HUVECs with 7 mmol/L NAC or 50 ng/mL leptin antagonists (LA) for 30min inhibited the increased expression of leptin and LEPR induced by HG in HUVECs. Furthermore, pretreatment with 7 mmol/L NAC or 50 ng/mL LA for 30 min also inhibited HG-induced injury, by increasing the cell viability and eNOS expression, and decreasing the inflammatory response and cleaved caspase-3 expression, the apoptotic cells and generation of intracellular ROS and a loss of MMP.
Conclusions NAC protects the HUVECs against HG-induced injury by inhibiting leptin/LEPR.
... Previous studies indicated that leptin played an important role in regulating body intake and energy metabolism. Leptin also had other functions, such as causing oxidative stress [15] , promoting inflammatory response [16] , and inducing vascular endothelial cell apoptosis [17] , which were closely related to the occurrence, development, and clinical prognosis of cardiovascular disease and diabetes [18,19] . Leptin resistance is manifested by an increase in plasma leptin levels, but the effect weakens or disappears. ...
Background The present study aimed to investigate whether N- acetylcysteine (NAC) protects human umbilical vein endothelial cells (HUVECs) against high glucose (HG)-induced injury by inhibiting leptin/leptin receptor (LEPR).
Methods HUVECs were treated with 40 mmol/L glucose for 24 h to establish a model of HG-induced endothelial cell injury; The cell viability was examined by cell counter kit-8 (CCK-8) assay; The expression levels of leptin, LEPR, cleaved caspase-3 and endothelial nitric oxide synthase (eNOS) were detected by western blot. The intracellular levels of reactive oxygen species (ROS) were tested by DCFH-DA staining followed by photofluorography. Tumor necrosis factor-α (TNF-α)、nuclear factor-kappa B (NF-κB) and intercellular adhesion molecule-1 (ICAM-1) were detected by enzyme-linked immunosorbent assay (ELISA). The number of apoptotic cells was observed by photofluorograph with Hoechst 33258 nuclear staining. Mitochondrial membrane potential (MMP) was obtained using JC-1.
Results The expression of leptin and LEPR began to significantly increase after exposure to 40 mmol/L HG for 24 h. Pretreatment of HUVECs with 7 mmol/L NAC or 50 ng/mL leptin antagonists (LA) for 30min inhibited the increased expression of leptin and LEPR induced by HG in HUVECs. Furthermore, pretreatment with 7 mmol/L NAC or 50 ng/mL LA for 30 min also inhibited HG-induced injury, by increasing the cell viability and eNOS expression, and decreasing the inflammatory response and cleaved caspase-3 expression, the apoptotic cells and generation of intracellular ROS and a loss of MMP.
Conclusions NAC protects the HUVECs against HG-induced injury by inhibiting leptin/LEPR.
... Future studies might also explore the potential interaction between leptin and the endocannabinoid system (ECS) in the neurobiology of panic disorder. Their close relationship has already been shown in a number of other clinical conditions, such as stroke (Avraham et al., 2010) and traumatic brain injury (Lopez-Rodriguez et al., 2016). Moreover, cannabinoid receptor-2 (CB2) knock-out mice demonstrate significantly reduced leptin levels (Deveaux et al., 2009) and leptin is a negative regulator of the synthesis of the endocannabinoid 2-arachidonoylglycerol (Di Marzo et al., 2001). ...
... In addition to estrogen, the adipokynin hormone, leptin, plays a role in severe energy depletion. Avraham et al. (2010) found that the expression of Sirt1 gene increased in the cortex after leptin administration, which was in line with the reduction of infarct volume. This finding suggested that Sirt1 expression protects cortical neurons by modulating energetic status (Avraham et al., 2010). ...
... Avraham et al. (2010) found that the expression of Sirt1 gene increased in the cortex after leptin administration, which was in line with the reduction of infarct volume. This finding suggested that Sirt1 expression protects cortical neurons by modulating energetic status (Avraham et al., 2010). ...
Silent mating type information regulation 2 homolog 1 (Sirt1), a nicotine adenine dinucleotide (NAD⁺)-dependent enzyme, is well-known in playing a part in longevity. Ischemic stroke is a major neurological disorder and is a leading cause of death and adult disability worldwide. Recently, many studies have focused on the role of Sirt1 in ischemic stroke. Numerous studies consider Sirt1 as a protective factor and investigate the signaling pathways involved in the process under ischemic stress. However, the answer to whether upregulation of Sirt1 improves the outcome of stroke is still a controversy. In this review, we discuss the role and mechanisms of Sirt1 in the setting of ischemic stroke.
... Several lines of evidence indicate that the beneficial effects of leptin involve CB2-dependent endocannabinoid signaling. Thus, leptin enhanced the expression of CB2 receptors in a stroke model 13 Immunostaining of sciatic nerves using leptin (a) and leptin receptor (b) specific antibodies. Shown are the areas just next to the injured site (ipsilateral) or middle of dissected nerve (contralateral). ...
... This genotype effect was reflected by a stronger activation of the leptin receptor-downstream signaling factor STAT3 in CB2-KOs. Our results are entirely consistent with the idea of a mutual positive interaction between cannabinoid and leptin signaling 9,13,15 . Thus, disrupting cannabinoid signaling via deletion of CB2 receptors is a likely cause for the observed deregulated leptin signaling. ...
Neuropathic pain typically appears in a region innervated by an injured or diseased nerve and, in some instances, also on the contralateral side. This so-called mirror image pain is often observed in mice lacking CB2 receptors after sciatic nerve injury, but the underlying mechanisms for this phenotype largely remain unclear. Here we focused on peripheral leptin signaling, which modulates neuropathic pain development and interacts with the endocannabinoid system. Leptin production is induced at the site of nerve injury in CB2-deficient mice (CB2-KO) mice and wild type controls (WT). However, induction of leptin receptor expression was only observed in the injured nerve of CB2-KO mice. This was paralleled by a stimulation of the leptin receptor-downstream STAT3 signaling and an infiltration of F4/80-positive macrophages. Interestingly, an upregulation of leptin receptor expression STAT3 activity and macrophage infiltration was also observed on the non-injured nerve of CB2-KO mice thus reflecting the mirror image pain in CB2-KO animals. Importantly, perineurally-administered leptin-neutralizing antibodies reduced mechanical hyperalgesia, blocked mirror image pain and inhibited the recruitment of F4/80-positive macrophages. These results identify peripheral leptin signaling as an important modulator of CB2 signaling in neuropathic pain.
