Joseph Weidenfeld

Hadassah Medical Center, Yerushalayim, Jerusalem, Israel

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Publications (153)473.77 Total impact

  • Malik Hasarmeh · Anna Itzik · Joseph Weidenfeld · Haim Ovadia
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    ABSTRACT: Objectives: The role of nitric oxide (NO) in modulating the blood-brain barrier (BBB) is not entirely clear. We examined the effect of different NO synthase (NOS) inhibitors and NO donors on the permeability of the BBB in animals with normally functioning brain blood vessels, following disruption by hyperosmotic mannitol and during immune inflammation. Methods: We administered L-NAME, aminoguanidine, S-methyl-thiocitrulline (SMT) and 7-indazole (NOS inhibitors) and NOR-4 (an NO donor) into the cerebral ventricle of rats. Disruption of the BBB was induced by intracarotid injection of mannitol (25%). Experimental autoimmune encephalomyelitis (EAE) was induced by brain homogenate. The extent of disruption was evaluated by Evans blue (2%) dye extravasation. Results: L-NAME (a nonspecific NOS inhibitor) and SMT (a neuronal and endothelial NOS inhibitor) increased mannitol-induced disruption of BBB. This effect was inhibited by NO donors. In animals with a normally functioning BBB, none of these inhibitors or NO donors caused a change in the permeability. 7-indazole (a specific neuronal NOS inhibitor) and aminoguanidine (an inducible NOS inhibitor) had no facilitatory effect on BBB permeability, either alone or in combination with hyperosmotic mannitol. Administration of L-NAME and SMT to rats with EAE significantly aggravated the clinical outcome. In contrast, the administration of NOR-4 diminished clinical signs of EAE. Conclusion: The NOS system does not play a role in BBB permeability in naïve animals. Only endothelial NOS takes part in the facilitation of BBB compromised by mannitol and EAE. Extrinsic NO decreases this facilitatory effect.
    No preview · Article · Dec 2015 · NeuroImmunoModulation
  • Joseph Weidenfeld · Anna Itzik · Haim Ovadia
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    ABSTRACT: Objective: The amygdala (AMG) plays a facilitatory role in the hypothalamic-pituitary-adrenal (HPA) axis. The effect of the AMG on the negative feedback exerted by glucocorticoids (GC) is not clear. We investigated the effect of repeated electrical stimulation of the AMG on the feedback action of GC upon the adrenocortical (AC) response to stressful stimuli. Methods: Rats received electrical stimulation into the central amygdalar nucleus once daily for 4 days. At days 5 and 12 after the onset of stimulation, rats were treated with dexamethasone (Dex) or vehicle and were exposed to either photic or acoustic stress stimuli, and serum corticosterone (CS) was measured. In another group of rats, we measured the binding of Dex to the hippocampal cytosol at 5 and 12 days after the AMG stimulation. Results: At 5 and 12 days after the onset of stimulation or a sham control, stress increased the serum CS level. In the sham group, Dex completely inhibited the CS response, but at 5 days after stimulation, it was significantly less effective in doing this. At day 12, Dex was as effective as in the control group. AMG stimulation delayed the return of CS response to basal levels and caused a significant decrease in the binding capacity of Dex to hippocampal cytosol. Conclusion: Electrical stimulation of the AMG caused a transient impairment of the feedback action of GC upon the stress response. This effect may be due to the decrease in hippocampal corticosteroid receptors. This suggests that the impaired GC feedback caused by AMG stimulation may be involved in the facilitatory effect of the AMG on the function of the AC axis.
    No preview · Article · Sep 2015 · NeuroImmunoModulation
  • Haim Ovadia · Tali Siegal · Joseph Weidenfeld
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    ABSTRACT: Background: Central nervous system (CNS) irradiation has detrimental effects which become evident within hours to few days and after a long latency of months and years. However, the delayed effect of irradiation on neuroimmune diseases has not been thoroughly examined. Objectives: We evaluated the delayed effects of irradiation on the course of experimental autoimmune encephalomyelitis (EAE), which is used as a model for neuroimmune inflammation and multiple sclerosis. Methods: Adult male rats were exposed to a dose of 15 Gy given to the thoracolumbar spinal cord. Six months later, EAE was induced by inoculation of rat spinal cord homogenate in complete Freund's adjuvant (CFA). The disease was evaluated by clinical, histopathological and immunological parameters. Results: Irradiated rats developed clinical signs of EAE earlier than the control group and their disease was much more severe. Unlike the control group, all rats in the EAE-irradiated group died within 5 days after the onset of clinical signs. Sections taken from irradiated rats showed diffuse and large hemorrhagic infiltrates of lymphocytes and granulocytes. In contrast, control rats displayed fewer infiltrates, which were less prominent and not hemorrhagic. Conclusions: CNS irradiation has a delayed effect that caused a marked aggravation of the clinical and pathological signs of EAE. The severity of the disease may be a consequence of the effect of irradiation on the CNS vascular bed and impaired blood-brain barrier.
    No preview · Article · Nov 2012 · NeuroImmunoModulation
  • Joseph Weidenfeld · Tali Siegal · Haim Ovadia
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    ABSTRACT: Background: Brain irradiation (BI) in humans may cause behavioral changes, cognitive impairment and neuroendocrine dysfunction. The effect of BI on the hypothalamic-pituitary-adrenal (HPA) axis is not fully understood. Objectives: To evaluate the effect of BI on HPA axis responses under basal and stressful conditions as well as following pretreatment with dexamethasone (Dex). Methods: Adult male rats were exposed to whole BI. HPA axis responses were examined at 2, 4, 9 and 20 weeks after BI. Histological evaluations of the irradiated rats and matched controls were conducted at 4 and 20 weeks after BI. Results: In contrast to the control group, the basal and stress-induced corticosterone levels were enhanced at 9 and 20 weeks after BI and the inhibitory effect of Dex was reduced. BI also caused hyposuppression of the adrenocortical response to stress. Histological assessment of the irradiated brains revealed hippocampal atrophy at 20 weeks after BI. The neuronal counts were lower only in the CA1 region of the irradiated brains. BI caused a decrease in the binding capacity of Dex to the hippocampal cytosolic fraction. Conclusions: Enhanced stress-induced HPA axis responses and the reduced effect of Dex suggest that BI has delayed effects on HPA axis responses as manifested by impairment of the negative feedback exerted by glucocorticoids (GCs). The mechanisms underlying these effects of BI are unknown. It is possible that the marked BI-induced damage in the hippocampus, which plays an important role in the regulation of the feedback effect of GCs, may cause abnormal HPA axis responses following BI.
    No preview · Article · Nov 2012 · NeuroImmunoModulation
  • J Weidenfeld · R R Leker · N Gai · A Teichner · D Bener · H Ovadia
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    ABSTRACT: We characterized the effect of acute ischemic stroke on the activation of the hypothalamic-pituitary-adrenal (HPA) axis and evaluated the role of glucocorticoids (GC) in the clinical outcome following ischemic stroke. Male spontaneous hypertensive rats underwent permanent middle cerebral artery occlusion (PMCAO) and developed a cortical infarct. At 4h post-PMCAO or sham operation, serum levels of ACTH and corticosterone (CS) were elevated 5 and 4 fold respectively as compared to controls and then returned to basal levels at 24h post surgery. In these experimental groups we found also a significant depletion of median eminence (ME)-CRH(41). In adrenalectomized (Adx) rats that underwent PMCAO the degree of motor disability and infarct volume was similar to that of intact rats. Administration of dexamethasone (Dex) to Adx-PMCAO rats significantly improved the motor disability and decreased the infarct volume. However, in sham-Adx with PMCAO, Dex had no effect on these two parameters. In rats with PMCAO or sham-PMCAO, brain production of PGE(2) was significantly increased. This effect was further enhanced in Adx-PMCAO rats and significantly inhibited by Dex. In conclusion, activation of the HPA axis following PMCAO is due to stress induced by surgery. This activation is mediated by hypothalamic CRH(41). Absence of endogenous GC or administration of Dex in naïve rats does not alter motor and pathological parameters in the acute stage following PMCAO. In contrast, administration of Dex significantly improved the outcome following cerebral ischemia in Adx rats which may be due to increased glucocorticoid receptors. Brain production of PGE(2) does not play an important role in the pathophysiology of the acute phase of cerebral ischemia.
    No preview · Article · Aug 2011 · Brain research
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    ABSTRACT: Herpes simplex virus-1 (HSV-1) is a common cause of viral encephalitis manifested by activation of the adrenocortical axis, fever and behavioral changes. We investigated the early effects of HSV-1 on constitutive (c) and inducible (i) nitric oxide synthase (NOS) activity in rat brain and in mixed glial cell culture. The effect of glucocorticoids (GCs) on NOS responses to HSV-1 was also determined. NOS activity was evaluated by the conversion of ³H-arginine to ³H-citrulline. Nitrites were measured in supernatants of activated glial cells. Under basal conditions, the highest cNOS activity was found in the cerebellum, while activity was much lower in the pons and negligible in the hypothalamus and hippocampus. Forty-eight hours after intracerebral injection of HSV-1, serum corticosterone was increased and NOS activity in the cerebellum and pons was inhibited. Adrenalectomy had no effect on the basal NOS activity but completely abrogated the inhibitory effect of HSV-1. Administration of the iNOS inhibitor aminoguanidine did not significantly change NOS activity, suggesting that the activity found in the cerebellum and pons can be attributed to the cNOS isoform. In mixed glial cell culture infected with HSV-1 and then activated with lipopolysaccharide, NOS activity and nitrite production were inhibited by 77 and 53%, respectively. These results suggest that brain NOS activity is inhibited in the early stages of HSV-1 infection and requires the presence of circulating GCs. HSV-1-induced brain NOS inhibition may play a role in neuronal viral invasion and in the activation of the adrenocortical axis.
    No preview · Article · Nov 2010 · NeuroImmunoModulation
  • Arielle Warner · Haim Ovadia · Nora Tarcic · Joseph Weidenfeld
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    ABSTRACT: Reciprocal pathways of interaction between the nervous and immune systems during stress may be regulated by stress-induced circulating glucocorticoids that act via type II glucocorticoid receptors (GRs). The aim of the present study was to investigate the effect of restraint stress on GRs in lymphocytes and the role of the sympathetic system in this effect. We used male Balb/c mice which were adrenalectomized 3 days before exposure to restraint stress (4 h). Specific binding of 3H-dexamethasone (Dex) and the expression of GR protein were measured in the cytosol of spleen cells. Restraint stress caused a significant increase in the maximal binding of 3H-Dex to GRs in the cytosol of spleen cells but not in the binding affinity. In correlation with this increase in binding, restraint stress caused an increase in the amount of GR protein. To establish the relation of the nervous system in this stress response, we blocked the autonomic innervations to the spleen with the ganglionic blocker chlorisondamine. This blocker abrogated the stress-induced increase in the binding of 3H-Dex to GRs and in the GR protein levels. Abrogation of the stress response was also achieved by blocking beta-adrenergic receptors. These results suggest that stress-induced increase in the level of GRs is mediated by the sympathetic nervous system via beta-adrenergic receptors. It is possible that stress modulation of lymphocyte GR levels may be implicated in the bidirectional communication between the nervous and the immune systems.
    No preview · Article · May 2010 · NeuroImmunoModulation
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    ABSTRACT: Several lines of evidence implicate the pro-inflammatory cytokine interleukin-1 (IL-1) in the etiology and pathophysiology of major depression. To explore the role of IL-1 in chronic stress-induced depression and some of its underlying biological mechanisms, we used the chronic mild stress (CMS) model of depression. Mice subjected to CMS for 5 weeks exhibited depressive-like symptoms, including decreased sucrose preference, reduced social exploration and adrenocortical activation, concomitantly with increased IL-1 beta levels in the hippocampus. In contrast, mice with deletion of the IL-1 receptor type I (IL-1rKO) or mice with transgenic, brain-restricted overexpression of IL-1 receptor antagonist did not display CMS-induced behavioral or neuroendocrine changes. Similarly, whereas in wild-type (WT) mice CMS significantly reduced hippocampal neurogenesis, measured by incorporation of bromodeoxyuridine (BrdU) and by doublecortin immunohistochemistry, no such decrease was observed IL-1rKO mice. The blunting of the adrenocortical activation in IL-1rKO mice may play a causal role in their resistance to depression, because removal of endogenous glucocorticoids by adrenalectomy also abolished the depressive-like effects of CMS, whereas chronic administration of corticosterone for 4 weeks produced depressive symptoms and reduced neurogenesis in both WT and IL-1rKO mice. The effects of CMS on both behavioral depression and neurogenesis could be mimicked by exogenous subcutaneous administration of IL-1 beta via osmotic minipumps for 4 weeks. These findings indicate that elevation in brain IL-1 levels, which characterizes many medical conditions, is both necessary and sufficient for producing the high incidence of depression found in these conditions. Thus, procedures aimed at reducing brain IL-1 levels may have potent antidepressive actions.
    Full-text · Article · Aug 2008 · Molecular Psychiatry
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    G Wolf · R Yirmiya · T Kreisel · I Goshen · J Weidenfeld · S Poole · Y Shavit
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    ABSTRACT: Exposure to stressful stimuli is often accompanied by reduced pain sensitivity, termed "stress-induced analgesia" (SIA). In the present study, the hypothesis that interleukin-1 (IL-1) may play a modulatory role in SIA was examined. Two genetic mouse models impaired in IL-1-signaling and their wild-type (WT) controls were employed. Another group of C57 mice was acutely administered with IL-1 receptor antagonist (IL-1ra). Mice were exposed to 2min swim stress at one of three water temperatures: 32 degrees C (mild stress), 20-23 degrees C (moderate stress), or 15 degrees C (severe stress); and then tested for pain sensitivity using the hot-plate test. Corticosterone levels were assessed in separate groups of WT and mutant mice following exposure to the three types of stress. Mild stress induced significant analgesia in the two WT strains and saline-treated mice, but not in the mutant strains or the IL-1ra-treated mice. Similarly, mild stress induced significantly elevated corticosterone levels in WT mice, and blunted corticosterone response in mutant mice. In contrast, both WT and mutant strains, as well as IL-1ra-treated mice, displayed analgesic and corticosterone responses following moderate and severe stress. Interestingly, the analgesic response to moderate stress was markedly potentiated in the mutant strains, as compared with their WT controls. The present results support our previous findings that in the absence of IL-1, stress response to mild stress is noticeably diminished. However, the analgesic response to moderate stress is markedly potentiated in mice with impaired IL-1 signaling, corroborating the anti-analgesic role of IL-1 in several pain modulatory conditions, including SIA.
    Full-text · Article · Aug 2007 · Brain Behavior and Immunity
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    ABSTRACT: Herpes simplex-1 (HSV-1) is a sporadic cause of viral encephalitis. We have previously demonstrated that corneal HSV inoculation markedly activates the hypothalamo-pituitary-adrenal (HPA) axis. This activation depends on host derived brain interleukine-1 and was resistant to pretreatment with dexamethasone (dex), possibly because immune factors such as pro-inflammatory cytokines can modify the binding capacity of glucocorticoids in the hippocampus. In the present study, we examined whether resistance of the HPA axis activation following intracerebral HSV-1 infection to dex-induced suppression is associated with modifications in hippocampal or pituitary glucocorticoids (GC) receptors or GC receptors in cultured astrocytes. Male rats were injected intracerebroventricularly with purified HSV-1 or vehicle. 48 h later, dex or vehicle was injected intraperitoneally. Rats were sacrificed 3.5 h later. ACTH and corticosterone (CS) were measured in the serum. Specific binding of 3H-dex was measured in the cytosolic fraction of the hippocampus and the pituitary. Dex failed to reduce ACTH and CS responses to HSV-1 infection. In contrast, dex significantly reduced ACTH and CS responses to acoustic neural stimuli. Infection with HSV-1 markedly reduced the hippocampal maximal specific binding of dex with no effect on the dissociation constant (Kd) values. HSV-1 had no effect on the binding of dex in the pituitary. Infection of cultured astrocytes with HSV-1 also reduced the maximal specific binding of dex, but increased the Kd value. The results suggest that HSV-1 induced GC resistance may be mediated by downregulation of GC receptors in hippocampal tissue. These results may clarify a mechanism responsible for GC resistance following immune challenges.
    Full-text · Article · Feb 2007 · Neuroendocrinology
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    ABSTRACT: We have reviewed the effects of two endogenous cannabinoid constituents, anandamide and 2-Ara-G1, and of two synthetic cannabinoids, HU-211 and HU- 210. Anandamide partly parallels THC in most CNS activities; the lack of published data prevents comparison of 2-Ara-G1 with THC. Anandamide probably serves as a mediator in motor functions, in memory and, judging from the effects of THC in humans on mood and cognition, in emotions. 2-Ara-G1 probably plays a role in the immune system. HU-210, which is one of the most potent cannabinoids prepared so far as evidenced by observations on sedation, catalepsy and hypothermia, will presumably continue to serve as a potent tool for cannabinoid investigations. HU-211 which is not cannabimimetic, but is an NMDA antagonist, may become a drug used in neuroprotection and possibly in medical conditions associated with high levels of glutamate, tumor necrosis factor, and/or with impaired function of the BBB.
    No preview · Article · Sep 2006 · CNS Drug Reviews

  • No preview · Article · May 2006 · Brain Behavior and Immunity
  • Benzion Beilin · Yehuda Shavit · Freda Dekeyser · Anna Itzik · Joseph Weidenfeld
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    ABSTRACT: This study examined the role of glucocorticoids (GC) and interleukin-1 (IL-1) in regulating the production of brain prostaglandin E(2) (PGE(2)) in response to surgical stress. Surgical stress was induced in rats by laparotomy or exploration of the carotid. PGE(2) ex vivo production was measured in the frontal cortex or central amygdala of adrenalectomized rats, or of rats treated with either the GC type II receptor blocker (RU38486) or synthetic GC (dexamethasone). IL-1 involvement in mediating PGE(2) response to surgical stress was examined in IL-1 receptor type I deficient (IL-1rKO) mice. Surgical stress elevated serum corticosterone and increased PGE(2) production by the frontal cortex and the central amygdala. A more pronounced PGE(2) response was found in adrenalectomized rats and in rats treated with RU38486, whereas administration of dexamethasone inhibited stress-induced PGE(2) production. IL-1rKO mice exhibited lower PGE(2) production in the frontal cortex under basal condition and failed to increase PGE(2) production in response to surgical stress. Surgical stress-induced production of brain PGE(2) is specifically regulated by GC via the mediation of type II corticosteroid receptors. Normal IL-1 signaling is required for the production of brain PGE(2) under basal conditions and in response to surgical stress.
    No preview · Article · Feb 2006 · NeuroImmunoModulation
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    Oren Shibolet · Ruslana Alper · Yaron Ilan · Joseph Weidenfeld
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    ABSTRACT: The hypothalamic-pituitary-adrenal (HPA) axis plays an important role in modulating immune reactions in inflammatory bowel disease. Our aim was to assess the role of the HPA axis in the pathogenesis of immunomediated colitis in mice. Trinitrobenzene sulfonic acid (TNBS) colitis was induced in Balb/c mice. Sham operation (sham+TNBS) or bilateral adrenalectomy (Adex+TNBS) was performed 3 days later. Control groups underwent adrenalectomy without colitis induction (Adex) or were untreated [naïve mice (Naïve)]. Mice were monitored for survival, weight loss, and macroscopic and microscopic scores of colitis. FACS analysis of CD4, CD8, natural killer T lymphocytes, and serum levels of adrenocorticotropic hormone (ACTH), corticosterone (CS), interferon-gamma (IFN-gamma), interleukin-10 (IL-10), and IL-1beta were measured. Production of prostaglandin E2 (PGE2) and binding capacity to glucocorticoid receptor (GR) in colonic mucosa were also assessed. By day 7 following induction of colitis there was a marked increase in ACTH and CS levels in the colitis as compared with the control group (86 +/- 6.5 pg/mL and 16 +/- 1.9 pg/mL, and 23.3 +/- 2 pg/mL and 2.8 +/- 0.8 pg/mL, respectively). There was a decrease in ACTH and CS levels by day 28 in the colitis group, but the levels were still significantly higher than the levels in controls. Adrenalectomy markedly exacerbated colitis. The macroscopic and microscopic scores increased from 2.79 +/- 0.03 and 2.0 +/- 0.1 in the sham+TNBS group to 3.3 +/- 0.3 and 3.2 +/- 0.3 in the Adex+TNBS group. Survival and weight loss correlated with these differences. A significant increase in IL-10, IFN-gamma, and PGE2 was noted in the Adex+TNBS group compared with the sham+TNBS group. Splenic CD4 lymphocytes decreased in the sham+TNBS and Adex+TNBS groups as compared with control groups (Adex and naïve). The CD8/CD4 ratio was significantly higher in the Adex+TNBS compared with the sham+TNBS group. Colitis also caused a significant decrease in the specific binding capacity of labeled dexamethasone to colonic mucosa. TNBS induced colitis activated the HPA axis and reduced the sensitivity of the inflamed mucosa to circulating glucocorticoids. Adrenalectomy markedly exacerbated TNBS-induced colitis. The effect was associated with changes in the peripheral CD8/CD4 ratio and with a TH1 cytokine shift. Our results suggest that adrenocortical hormones play an important role in the regulation of the immune system in experimental colitis.
    Full-text · Article · Jan 2006 · Inflammatory Bowel Diseases
  • E Fride · R Suris · J Weidenfeld · R Mechoulam
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    ABSTRACT: Previous studies have suggested that the endocannabinoid CB1 receptor (ECBR) system is involved in stress. However, the nature of this association is complex. Here, we investigated the role of CB1 receptors in the response to stress by comparing the effects of various stress modalities in CB1-/- receptor deficient and wild-type mice, at adulthood and during early development. Response to acute stress was assayed by plasma corticosterone (CS) and adrenocorticotrophic hormone (ACTH), USVs and motor inhibition. The response to repeated stress was assessed by USVs and motor inhibition. Since repeated bell stress seemed to cause a cumulative fear in CB1 receptor knockout mice, these behavioral responses were also compared to those observed after a single severe stress (forced swimming). In wild-type, but not in CB1 receptor knockout mice, bell stress-induced elevations of ACTH and CS were significant. The first exposure to bell stress had no significant effect on USVs or mobility. Upon repeated exposures, significant suppression of USVs, together with behavioral inhibition, were observed in CB1 knockout but not in wild-type mice. Swim stress inhibited USVs in the knockout animals, and the profound motor inhibition displayed by all animals was greater and more prolonged in the CB1-/- mice. Since the knockout mice lack the CB1 receptor throughout pre- and postnatal life, the stress response in pups was also assayed (by separation-induced USVs). Wild-type pups displayed the characteristic developmental peak in USV emissions; it was completely lacking in knockout pups. We conclude that acutely, the absence of CB1 receptors reduces the neuroendocrine response and does not affect the behavioral response to moderate stress. However, upon repeated stress or acute severe stress, CB1 receptor deficiency causes persistent behavioral inhibition. Finally, the CB1 receptor plays a role in modulating the stress response from an early age. These observations suggest that CB1 receptors participate in the mediation of the stress response and that the absence of these receptors results in a greater vulnerability to stress. We suggest that the stress-induced endocrine and behavioral suppression in CB1 receptor deficient mice may serve as a model for some forms of post-traumatic stress disorder (PTSD). Further, the role of CB1 receptors in coping with stress is a lifelong function. Finally, although equivalent research has not been performed in human infants, the postnatal suppression of the stress response in CB1 receptor knockout pups may have implications when cannabinoid-based therapy is considered for children.
    No preview · Article · Oct 2005 · Behavioural Pharmacology
  • Joseph Weidenfeld · Michael E Newman · Anna Itzik · Shaul Feldman
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    ABSTRACT: We have examined the effect of lesions of the central and medial amygdala on the pituitary-adrenal responses to noradrenergic stimulation and to the injection of glutamate into the paraventricular nucleus. Bilateral lesions of the amygdalar nuclei inhibited adrenocorticotrophic hormone and corticosterone responses to electrical stimulation of the ventral noradrenergic bundle, and to the injection of the alpha1-adrenergic agonist phenylephrine or glutamate. These results suggest that the amygdala may facilitate the stimulatory roles of noradrenaline and glutamate on the adrenocortical axis. The data contribute to understanding the mechanisms by which the amygdala is involved in the function of this axis.
    No preview · Article · Sep 2005 · Neuroreport
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    ABSTRACT: Surgical stress is the combined result of tissue injury, anesthesia, and postoperative pain. It is characterized by elevated levels of adrenocorticotropin (ACTH), corticosterone (CS), and elevated levels of prostaglandin E2 (PGE2) in the periphery and in the spinal cord. The present study examined the effects of perioperative pain management in rats undergoing laparotomy on serum levels of ACTH, CS, and on the production of PGE2 in several brain regions, including the amygdala. The amygdala is known to modulate the pituitary-adrenal axis response to stress. We, therefore, also examined the effects of bilateral lesions in the central amygdala (CeA) on laparotomy-induced activation of the pituitary-adrenal axis in rats. In the first experiment, rats either underwent laparotomy or were not operated upon. Half the rats received preemptive analgesia extended postoperatively, the other received saline. ACTH, CS serum levels, and ex vivo brain production of PGE2 were determined. In the second experiment, rats underwent bilateral lesions of the CeA. Ten days later, rats underwent laparotomy, and ACTH and CS serum levels were determined. Laparotomy significantly increased amygdala PGE2 production, and CS and ACTH serum levels. This elevation was markedly attenuated by perioperative analgesia. Bilateral CeA lesions also attenuated the pituitary-adrenal response to surgical stress. The present findings suggest that the amygdala plays a regulatory role in mediating the neuroendocrine response to surgical stress. Effective perioperative analgesia attenuated the surgery-induced activation of pituitary-adrenal axis and PGE2 elevation. The diminished elevation of PGE2 may suggest a mechanism by which pain relief mitigates pituitary-adrenal axis activation.
    No preview · Article · Jul 2005 · Brain Research
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    Joseph Weidenfeld · Anna Itzik · Irit Goshen · Raz Yirmiya · Tamir Ben-Hur
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    ABSTRACT: The amygdala is known to regulate neuroendocrine and behavioral responses to a variety of stimuli. Herpes simplex virus-1 (HSV-1) is the common cause of viral encephalitis, manifested by hypothalamic-pituitary-adrenal (HPA) axis activation, fever, hypermotor activity and aggression. We examined here the role of the central amygdala (cAMG) in regulating the HPA axis function, febrile and behavioral responses to HSV-1 infection in rats. Bilateral electrolytic lesions were performed in the cAMG. HSV-1 encephalitis was induced by intracerebroventricular (ICV) inoculation of purified virions. Motor activity and body temperature were examined by a biotelemetric system. ICV inoculation of HSV-1 caused a marked time-dependent increase in serum corticotropin (ACTH) and corticosterone at 4 and 24 h post-infection. These responses were attenuated in rats with bilateral lesions of the cAMG. HSV-1 infection induced fever, motor hyperactivity and aggressive behavior. These responses were also attenuated in rats with cAMG lesions. The cAMG plays an important role in mediating the neuroendocrine, febrile and behavioral responses to HSV-1 infection.
    Full-text · Article · Feb 2005 · Neuroendocrinology
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    ABSTRACT: We examined whether immunization with the nonpathogenic strain R-15 of herpes simplex virus-1 (HSV-1) may prevent the clinical and neuroendocrine changes induced by the pathogenic HSV-1 strain Syn17+. Inoculation of strain Syn17+ to control rats induced fever, marked motor hyperactivity and aggressive behavior, and increased serum ACTH, corticosterone (CS) and brain prostaglandin-E2 production. Mortality was 100%. Immunization with strain R-15 prior to challenge with Syn17+ induced the production of neutralizing antibodies to HSV-1 Syn17+, and abolished the above clinical and neuroendocrine changes. Mortality was completely prevented. These results indicate that immunization with HSV-1 strain R-15 protects rats from lethal HSV-1 encephalitis and prevents its clinical and neurochemical manifestations.
    Full-text · Article · Aug 2004 · Journal of Neuroimmunology
  • H Weidemann · N Salomon · T Avnit-Sagi · J Weidenfeld · H Rosen · D Lichtstein
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    ABSTRACT: Digitalis-like compounds (DLC) are steroidal hormones that are synthesized in, and released from, the adrenal gland, whose regulation may be directed by the hypothalamic-pituitary-adrenal (HPA) axis. Increasing evidence points to antitumour properties of these compounds and we hypothesized that the establishment of tumours in athymic nude mice may be facilitated by an abnormal synthesis or secretion of DLC. To explore this hypothesis, DLC concentrations were determined in the plasma, and in adrenal and hypothalamic tissues of nude compared to normal mice under basal conditions, and 30 min after a stress stimulus (i.p. injection of 100 micro l saline) with or without additional adrenocorticotropic hormone (ACTH) 1 micro g/per animal. Simultaneously, plasma corticosterone and serum adrenocorticotropic hormone (ACTH) concentrations were analysed. The basal DLC concentrations were similar in the plasma and the hypothalamus of both strains, whereas the basal adrenal DLC concentration was significantly lower in the nude mice compared to normal mice. The stress stimulus induced in normal mice a significant increase in DLC concentrations in the adrenal gland, the plasma and the hypothalamus. However, in nude mice, it caused an increase only in the adrenal gland and the hypothalamus, whereas the plasma DLC concentration was not affected. In both strains, the administration of ACTH in addition to injection stress did not provoke a further increase in DLC concentrations while inducing a significant increase in plasma corticosterone concentration. Regardless of the applied stimulus, the nude mice expressed significant lower DLC concentrations in the adrenal gland and the plasma compared to normal mice. The low basal adrenal DLC concentration in nude mice and their impaired DLC response towards stress- and ACTH stimulation both support an involvement of DLC in tumorigenesis.
    No preview · Article · Jun 2004 · Journal of Neuroendocrinology

Publication Stats

4k Citations
473.77 Total Impact Points


  • 1982-2015
    • Hadassah Medical Center
      • Department of Neurology
      Yerushalayim, Jerusalem, Israel
  • 1977-2012
    • Hebrew University of Jerusalem
      • • Department of Neurobiology
      • • Department of Psychology
      • • Department of Pharmacology
      • • Hadassah Medical School
      Yerushalayim, Jerusalem, Israel
  • 1982-1999
    • Bikur Holim Hospital,
      Yerushalayim, Jerusalem, Israel
  • 1995
    • Institut Pasteur
      Lutetia Parisorum, Île-de-France, France