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PubMed1983

Actions of substance P, MIF, TRH and related peptides in the substantia nigra, caudate nucleus and nucleus accumbens.

Neurones in the substantia nigra were found to be sensitive to iontophoretically applied substance P, substance P 1-9 methyl ester and substance P 1-9 amide. Substance P 1-2, 4-9 and 5-9 methyl esters, thyrotropin releasing hormone (TRH), Pyroglutamyl-histidyl-2 methyl prolineamide (methyl TRH), Pyroglutamyl-histidyl-2 methyl prolineamide (methyl TRH), histidyl-proline-diketopiperazine (His-Pro) and MSH releasing inhibiting factor (MIF) were without effect on neurones in this area. Thyrotropin releasing hormone (TRH), methyl TRH, His-Pro and MIF were inactive on neurones in the caudate nucleus and nucleus accumbens. Bilateral injections of substance P and substance P 1-9 methyl ester into the ventral tegmental area (VTA) of conscious rats produced locomotor activity, while similar injections of substance P 4-9 and 5-9 methyl esters did not. The locomotor activity produced by amphetamine was prolonged by TRH, while MIF was devoid of such activity. The data suggest that substance P and substance P 1-9 have similar effects in the substantia nigra, although the mechanism of action is unclear. Thyrotropin releasing hormone and MIF probably do not have acute actions in the brain areas tested.

Animals↗
PubMedDate not supplied

Alpha-MSH and MIF-I effects on catecholamine levels and synthesis in various rat brain areas.

Attempts were made to find a biochemical correlate with previously observed behavioral alterations after administration of alpha-melanocyte-stimulating hormone (MSH) and MSH release-inhibiting factor (MIF-I). Brains of intact and hypophysectomized (hypox) rats were analyzed for endogenous catecholamine levels and the disappearance rate of endogenous norepinephrine (NE) after treatment with the tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine (AMPT). The studies undertaken show the following: (1) After the injection of MSH (100 mug/kg IP daily x 3) and AMPT, samples in different groups of intact and hypox rats were taken at 0, 1, 2, 4 and 6 hrs in 7 different brain areas. In the mid-brain area for the intact group of rats, the rate of disappearance of NE was faster and for the hypox rats it was slower than the rate for control rats not treated with the peptides. NE levels in the same area at time 0 were 11 percent lower than controls in hypox rats and unchanged in unoperated animals. (2) After the injection of MIF-I (20 mg/kg IP daily x 3) in similar experiments as with MSH, a reduced rate (p less than 0.05) of NE disappearance for the first 4 hr and an increased rate (p less than 0.05) of NE disappearance for the last 2 hr of the experiments occurred for both the intact and hypox rats in the mid-brain area where endogenous NE levels were lowered by 11 and 12 percent at 0 min. In no other brain areas were alterations in NE breakdown found in both the intact and hypox rat groups. Behavioral changes have been found previously under similar experimental conditions in both intact and hypox rats. (3) Rates of dopamine disappearance in experiments similar to those described for NE disappearance indicated that in the striatal brain area no change was found in the intact rats after either MSH or MIF-I, whereas a decrease in DA disappearance was found for hypox rats during the six hour experimental period only after MSH. The results indicate that a correlation between behavioral changes, rates of disappearance and endogenous levels of NE in the mid-brain area may occur after MIF-I at the times examined but that a similar correlation for MSH did not appear likely.

Animals↗
PubMed1979

MIF-I's differential actions as an opiate antagonist.

The effects of MIF-I (Pro-Leu-Gly-NH2) were examined in three experimental conditions in which the opiate antagonist naloxone is active. MIF-I was found to block the analgesic effects of enkephalins and also morphine in the tail-flick test but not in the vas deferens assay. Unlike naloxone, MIF-I did not seem to reduce food intake in VMH-lesioned rats. The results suggest the possibility that MIF-I may represent a class of naturally occurring opiate antagonists with varying activities in independent situations.

Analgesics↗
PubMed1982

Similar antagonism of morphine analgesia by MIF-1 and naloxone in Carassius auratus.

Prolyl-leucyl-glycinamide (MIF-1), the C-terminal tripeptide of oxytocin, and naloxone were administered intracranially (IC) to goldfish (Carassius auratus) in doses of 0.001, 0.01, 0.1, 1.0 and 10.0 mg/kg and compared to a diluent control group for their ability to reduce the effects of morphine (30 mg/kg IC) in an assay measuring analgesia to electric shock. Threshold levels of pain were determined by the voltage necessary to produce an agitated swimming response (ASR). Both MIF-1 and naloxone were found to significantly reduce the analgesic effects of morphine when compared to the diluent control group. Similar dose-response curves in an apparent sine-wave pattern were noted with both MIF-1 and naloxone when comparisons were made both at 20 minutes after administration of morphine and over the entire 150 minutes of the experiment. The results support the evidence that MIF-1 can act as an opiate antagonist.

Analgesia↗
PubMed1989

MIF-1 is active in a chronic stress animal model of depression.

MIF-1 was tested in an animal model of depression that used unpredictable chronic stress. In this paradigm, rats received either no stressors or a daily protocol of a variety of stressors for 20 days, during which time daily, intraperitoneal injections of various compounds were given. The tricyclic antidepressant imipramine (5 mg/kg) and low doses (0.1 and 1.0 mg/kg) of MIF-1 significantly increased activity and decreased defecation in an open field on day 21. No dose of naloxone (0.01-10.0 mg/kg) acted as an antidepressant. A high dose (10.0 mg/kg) of MIF-1 significantly increased the effects of chronic stress and produced hyperalgesia. Chronically-stressed rats were significantly more analgesic than controls. The results indicate that MIF-1 can act as an antidepressant in this model.

Animals↗
PubMed1994

Improvement in major depression after low subcutaneous doses of MIF-1.

In this double-blind pilot study, 20 significantly depressed patients who all met the DSM-III R criteria for major depression were given a single subcutaneous injection of either 10 mg MIF-1 (Pro-Leu-Gly-NH2) or placebo on each of 5 consecutive days. Treatments were reversed for a second week of 5 consecutive daily injections. At the end of the first week, the group receiving MIF-1 was significantly improved on all rating scales as compared with the group receiving placebo. Eight out of 9 patients receiving MIF-1 showed marked improvement (score < or = 7 on the Hamilton Scale) as compared with only 2 of 11 patients receiving saline (P < 0.01). Administration of MIF-1 during the second week to the patients who had received placebo during the first week resulted in substantial improvement so that by the end of the second week the two groups were indistinguishable.

Adult↗
PubMed1980

Interaction of MIF-I or alpha-MSH with D-amphetamine or chlorpromazine on thermoregulation and motor activity of rats maintained at different ambient temperatures.

Administration of several doses of MIF-I or alpha-MSH did not modify colonic temperature or the level of motor activity of rats in ambient temperatures of 4 degree or 20 degrees C. However, the thermoregulatory but not motor effects of the interaction between MIF-I or alpha-MSH with d-amphetamine were dependent upon ambient temperature. At 4 degree C, 1.0 mg/kg of both peptides enhanced the d-amphetamine-induced hypothermia, but at 20 degrees C both peptides blocked the hyperthermic effects of d-amphetamine. The hypothermic effect of chlorpromazine (CPZ) at 4 degree C and 20 degrees C was blocked by 1.0 mg/kg MIF-I but not by 1.0 mg/kg alpha-MSH. No linear dose response relationships between various doses of MIF-I or alpha-MSH and thermal responses were found. Administration of melanin or the use of hypophysectomized rats did not alter the significant interactions observed after peripheral injections.

Animals↗
PubMedDate not supplied

Attenuation of morphine analgesia by alpha-MSH, MIF-I, melatonin and naloxone in the rat.

In two experiments the effects of the pituitary peptide alpha-MSH, the hypothalamic tripeptide MIF-I (P-L-G-NH2) and the pineal hormone melatonin were investigated on the attenuation of morphine analgesia measured by a tail flick test. In Experiment 1, alpha-MSH had minimal effect on morphine analgesia, whereas, MIF-I and melatonin clearly delayed the onset of morphine analgesia, and melatonin also shortened the duration of analgesia. Experiment 2 was designed to investigate the possible synergistic effect of MIF-I and melatonin. The combined treatment of MIF-I and melatonin significantly delayed the onset of morphine analgesia, and melatonin alone shortened the duration of analgesia. The relationships among the pituitary, hypothalamus and the pineal for the modulation of pain and response to morphine were discussed.

Analgesia↗
PubMedDate not supplied

The effect of oxytocin and fragment (MIF-I) on the development of tolerance to hypothermic and hypnotic action of ethanol in the rat.

The daily pretreatment of rats with oxytocin (OXY) or MIF-I prior to ethanol (Et-OH) administration markedly altered the alcohol tolerance when tested on the fifth day of treatment. OXY (800 and 2400 nmole/kg SC) and MIF (800 nmole/kg SC) inhibited the development of tolerance to the hypnotic effect of Et-OH. MIF at this dose also inhibited the tolerance to the hypothermic effect. Only OXY in the dose of 800 nmole/kg suppressed hypothermia in an acute experiment with Et-OH and produced by itself hypothermia after acute administration (2400 nmole/kg). The tolerance to this last effect developed after four days of peptide treatment. The results indicate that OXY and MIF-I can influence the processes of development of tolerance to some central depressive effects of Et-OH in rats.

Animals↗
PubMedDate not supplied

Interactions between the antiopiate Tyr-MIF-1 and the mu opiate morphiceptin at their respective binding sites in brain.

The interactions between Tyr-MIF-1, a brain peptide with antiopiate activity, and the beta-casomorphins, a family of peptides derived from milk protein with opiate activity, were investigated by in vitro binding assays. Specific binding of 125I-Tyr-MIF-1 to rat brain membranes was displaced with high potency by beta-casomorphin, morphiceptin, and the morphiceptin analog PL017 but not by the analgesically inactive analog D-Pro2-morphiceptin or by several other ligands for classical delta, kappa, or sigma opiate receptors. In addition, Tyr-MIF-1 displaced 125I-morphiceptin from its binding sites in brain with affinities similar to those of unlabeled morphiceptin and PL017. These results, which include the first demonstration of a binding site in brain for labeled morphiceptin, indicate that brain antiopiate Tyr-MIF-1 and the beta-casomorphin derived peptides with opiate activity may share a common binding site or cross-react at each other's site. This suggests a possible mechanism of action for endogenous antiopiate-opiate interactions.

Analgesics↗
PubMedDate not supplied

MIF-1 antagonizes warm-, but not cold-water stress-induced analgesia: dissociation from immobility.

Forced swimming in warm or cold water can lead to immobility and analgesia in mice. In this report we demonstrate that the peptide MIF-1 (Pro-Leu-Gly-NH2) was able to attenuate the analgesia induced by swimming in warm water, but not that induced by swimming in cold water. In addition, we show that the analgesia and the immobility may be differentially mediated since MIF-1 was able to reduce the immobility at doses different from those necessary to reduce the analgesia. These results confirm previous research indicating that MIF-1 may act as an anti-opiate and further demonstrate that MIF-1 affects analgesia induced by stress.

Analgesia↗
PubMed1994

Expression of the FOS proto-oncogene protein in brain after ICV administration of Tyr-W-MIF-1 (Tyr-Pro-Trp-Gly-NH2).

Tyr-W-MIF-1 is a tetrapeptide recently isolated from brain that has opiate modulating activity. In this study, we used immunocytochemical (ICC) detection of FOS proto-oncogene protein to map brain areas activated by an ICV injection of Tyr-W-MIF-1 (200 micrograms). The analgesic effect of the peptide, which lasted 1 h, was confirmed in each rat with the tail flick test. FOS was activated in several limbic structures, including the cingulate and infralimbic cortex, nucleus accumbens, and central nucleus of the amygdala. FOS activation also occurred in several diencephalic nuclei, including the supraoptic, paraventricular, and periventricular nuclei of the hypothalamus, and the paraventricular nucleus of the thalamus. Several activated areas contained mu-opiate receptors. However, despite the known selectivity of Tyr-W-MIF-1 for mu receptors, FOS immunoreactivity was also induced in nuclei of the amygdala, hypothalamus, and thalamus, where concentrations of kappa receptors were high but those of mu and delta receptors were not detected. The results show that Tyr-W-MIF-1 induces FOS activation in several brain areas, including but not limited to, areas associated with nociception and stress-induced analgesia.

Analgesia↗
PubMed1981

Mu and delta opiate receptors in rat brain are affected by GTP but not by MIF-1.

The possible competition of MIF-1 (Pro-Leu-Gly-NH2) with 3H-naloxone or 3H-D-Ala-D-Leu-enkephalin (DADLE) for mu and delta opiate receptors in the rat striatum was examined under conditions of varying temperatures and concentrations of sodium and GTP. MIF-1, in concentrations ranging from 10(-14) to 10(-3) M, failed to compete with either 3H-DADLE or 3H-naloxone for delta or mu receptors, GTP (2 microM) facilitated binding (17.7 +/- 1.9%) at all concentrations of MIF-1 in the 1H-DADLE assay; unexpectedly, GTP facilitated binding in the 3H-naloxone assay (11.5 +/- 1.3%) under conditions used to potentiate antagonist binding (addition of NaCl and incubation at 4 degrees C). GTP showed optimal facilitation at a concentration of about 2 microM in both the 3H-DADLE and 3H-naloxone "antagonist" conditions. At higher doses of GTP, 3H-naloxone binding remained high, but 3H-DADLE binding decreased to near or below control values. MIF-1 did not affect these GTP responses, indicating further the lack of effect of this peptide on opiate binding.

Animals↗
PubMed1981

Radioimmunoassayable N-Tyr-MIF-1-like activity in rat brain is increased by pinealectomy.

Levels of N-Tyr-MIF-1-like immunoreactivity were measured in rat brain by radioimmunoassay (RIA). Although the highest levels were found in the pineal and hypothalamus, the striatum and thalamus also contained significantly more immunoreactivity than the other parts of the brain. Since oxytocin cross-reacts 5.4% with the antibody for N-Tyr-MIF-1, oxytocin-like immunoreactivity was also measured by RIA, but could not account for the levels of radioimmunoassayable N-Tyr-MIF-1 found in these experiments. There was a significant increase in N-Tyr-MIF-1-like immunoreactivity after pinealectomy, a tendency for a decrease after stress, but essentially no change after hypophysectomy. A diurnal rhythm was observed with the highest levels at night and lowest levels during the day. The results demonstrate the presence in brain tissue of a novel immunoreactive peptide, the levels of which can be altered by neuroendocrine manipulations.

Animals↗
PubMed2004

Mechanisms and effectors of MIF-dependent promotion of tumourigenesis.

The importance of secreted cytokines and growth factors in the development and promotion of malignancies is often underestimated. Many different soluble, extracellular gene products participate in processes that collectively contribute to the growth and survival of a developing neoplasm. These secreted molecules can, directly or indirectly, play a central role in uncontrolled tumour cell division, angiogenic stimulation or suppression of tumour cell immune surveillance. One of the first cytokine activities ever described, macrophage migration inhibitory factor (MIF), is unique to these soluble mediators in that it participates in all of these pro-tumourigenic processes. Overexpressed in most tumour types examined, MIF has been shown to promote malignant cell transformation, inhibit tumour cell-specific immune cytolytic responses and strongly enhance neovascularization. Despite this broad array of activities, the elucidation of molecular and cellular mechanisms involved in MIF-dependent bioactions has remained elusive. This review will focus on recently characterized phenotypes and mechanistic effectors thought to be associated with MIF-dependent promotion of neoplastic processes and discuss their relative importance in carcinogenesis.

Animals↗
PubMed2004

Structure-based rationalization of antitumor drugs mechanism of action by a MIF approach.

Structural patterns for antitumor drugs, evidenced by means of a molecular interaction field (MIF) approach using grid independent descriptors (GRIND), resembled closely those of a previous independent pharmacological classification based on their antitumor mechanism of action. For topoisomerase II inhibitors, antimitotic agents and DNA antimetabolites, systematic structural patterns were evidenced by MIF and the structural features of "outliers" in these classes corresponded to peculiar pharmacological mechanisms of action supported by literature evidences. Alkylating agents and DNA/RNA antimetabolites, interacting with a large variety of targets by different molecular mechanisms, did not exhibit clustering in the structure-based MIF approach. Moreover MIFS were able to point out similarities between drugs which, in spite of apparent dramatic differences in chemical structure, exhibit the same pharmacological behaviour.

Antineoplastic Agents↗
PubMed2005

Plant-derived anti-inflammatory compounds affect MIF tautomerase activity.

The cytokine macrophage migration inhibitory factor (MIF) has recently emerged as a crucial factor in the pathogenesis of rheumatoid arthritis (RA). It is debated whether the MIF mediated tautomeric conversion of either phenylpyruvate or of its other phenolic substrates is implicated in the pro-inflammatory action of this cytokine. Traditional herbal remedies have been used for centuries to alleviate inflammatory ailments of many kinds including arthritis. Several of their active ingredients identified are mono- or poly-phenol derivatives. In the present study the effect of some anti-inflammatory plant phenols on MIF mediated tautomerism of phenylpyruvate was investigated. Curcumin and caffeic acid were found to be the most potent inhibitors, exhibiting IC(50) values in the submicromolar range in the ketonase assay. Resveratrol and umbelliferon were almost as potent inhibitors as the antipyretic-analgetic drug acetaminophen. Our results reveal MIF as a possible target for the herbal anti-rheumatic agents.

Animals↗
PubMed2006

Investigating disease susceptibility and the negative correlation of schizophrenia and rheumatoid arthritis focusing on MIF and CD14 gene polymorphisms.

Schizophrenia and rheumatoid arthritis (RA) are both chronic diseases with an estimated genetic component of 60%. While RA is a well-known autoimmune inflammatory joint disease, recent data point to an active immune process also being involved in schizophrenia. Several studies confirmed the negative association between schizophrenia and RA, indicating genetic factors that predispose to the one disorder, while protecting from the other. Macrophage migration inhibitory factor (MIF) and the monocytes surface receptor CD14 are involved in the development and maintenance of chronic inflammation. We therefore investigated if the -G173C single nucleotide polymorphism (SNP) and the tetranucleotide repeat CATT (5 - 8) at position -794 of the MIF gene and the CD14 - C159T transition are candidates for genetic liability to schizophrenia and RA or could explain the negative association between them. In our study 157 schizophrenic patients, 119 patients suffering from RA, and 225 healthy individuals were genotyped. All subjects were Caucasians. The CD14- and MIF-genotypes were equally distributed in all three groups. From our results, we cannot confirm the hypothesis that the investigated genetic mutations within the MIF and/or the CD14 gene are involved in the aetiology of either disease or could explain the negative correlation of schizophrenia and RA.

Adolescent↗