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PubMed1989

MIF-1 and Tyr-MIF-1 augment muscimol-stimulated chloride uptake in cerebral cortex.

The peptides MIF-1 (Pro-Leu-Gly-NH2) and Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2) recently have been found to augment the effects of gamma-aminobutyric acid (GABA) on benzodiazepine receptor binding and chloride channel binding (Tyr-MIF-1) at the GABAA receptor complex. To determine whether these peptides affect the function of this complex in chloride transport, we evaluated chloride uptake stimulated by the GABA analog muscimol in synaptoneurosome preparations. In mice treated with either MIF-1 or Tyr-MIF-1 (1 mg/kg IP), maximal chloride uptake in cortex was increased compared with controls. The two peptides had similar effects in cortical preparations, but in cerebellum neither peptide altered chloride uptake. No differences from controls were observed in cortical synaptoneurosomes treated in vitro with either MIF-1 or Tyr-MIF-1. These results suggest that the brain peptides MIF-1 and Tyr-MIF-1 alter function at the GABAA receptor complex, perhaps by binding at a specific peptide receptor.

Animals↗

PubMed1994

Mu, delta, and kappa opiate receptor binding of Tyr-MIF-1 and of Tyr-W-MIF-1, its active fragments, and two potent analogs.

The relative binding to mu, delta, and kappa opiate receptors was characterized for the brain peptides Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2), Tyr-W-MIF-1 (Tyr-Pro-Trp-Gly-NH2), and two fragments of Tyr-W-MIF-1 (Tyr-Pro-Trp and Tyr-Pro-Trp-Gly) previously shown to have antagonist as well as agonist activity in the guinea pig ileum. Tyr-MIF-1 had relatively low affinity (Ki = 1 microM at the mu site) but high selectivity (400- and 700-fold greater affinity for mu over delta and mu over kappa binding). Tyr-W-MIF-1 (Ki = 71 nM at the mu site) showed higher affinity binding to all three sites than Tyr-MIF-1 while retaining 200-fold selectivity for mu over delta and kappa receptors. The affinity of the fragments of Tyr-W-MIF-1 was lower for mu but higher for delta receptors. We also tested two cyclized analogs of Tyr-W-MIF-1 that were about 200-fold more active than the parent compound in producing analgesia. These analogs showed higher affinity binding to all three opiate receptors. One of the analogs showed binding affinity to mu sites (Ki = 1.3 nM) that was within 3-fold of that of the potent analog of enkephalin, DAMGO. Thus, brain peptides with an N-terminal Tyr-Pro, rather than the Tyr-Gly-Gly-Phe sequence typical of other endogenous opiates, can provide high selectivity for mu opiate receptors. Analogs based on one of them, Tyr-Pro-Trp-Gly-NH2, show high affinity as well as potent analgesic activity.

Amino Acid Sequence↗

PubMedDate not supplied

Inhibitory influences of MIF-1 (PLG) and Tyr-MIF-1 (YPLG) on aggression and defeat-induced analgesia in mice.

The effects of prolyl-leucyl-glycinamide (MIF-1, PLG), tyrosine-prolyl-leucyl-glycinamide (Tyr-MIF-1, YPLG) and the exogenous opiate antagonist, naloxone, on aggressive interactions and defeat-induced analgesia were examined in male mice. All three substances reduced the number of bites required to obtain defeat in subordinate mice during aggressive encounters, as well as blocking subsequent defeat-induced analgesia. Tyr-MIF-1 had significantly greater inhibitory effects than MIF. These results suggest that both MIF and Tyr-MIF-1 may function as endogenous opioid antagonists and have inhibitory influences on aggression, with the antagonistic effects of Tyr-MIF-1 being more potent than those of MIF-1.

Aggression↗

PubMed1994

Differential effects of Tyr-MIF-1, MIF-1, and naloxone on peptide YY-induced hyperphagia.

Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2) and MIF-1 (Pro-Leu-Gly-NH2) act as opiate antagonists in various behavioral systems including ingestion. Central injection of peptide YY (PYY) elicits a powerful feeding response in satiated rats, and the opioid antagonist naloxone decreases eating in a variety of conditions including PYY-stimulated eating. Therefore, the aim of this study was to examine the effects of Tyr-MIF-1 and MIF-1 as opiate antagonists on a naloxone-sensitive PYY model of hyperphagia. Naloxone at doses of 1.0 and 10.0 mg/kg, SC, decreased hyperphagia induced by 2.4 micrograms PYY injected in the PVN. MIF-1 and Tyr-MIF-1 had no effect on PYY-induced eating at doses comparable to naloxone (0.1 to 10.0 mg/kg, IP). These results suggest that in this model of eating behavior, Tyr-MIF-1 and MIF-1 do not act as opiate antagonists.

Animals↗

PubMed1990

MIF-1 and Tyr-MIF-1 do not alter GABA binding on the GABAA receptor.

The endogenous brain peptides MIF-1 and Tyr-MIF-1 have been reported to alter binding at several sites on the GABAA receptor. To determine whether these peptides affect binding at the GABA site, we assessed effects of MIF-1 and Tyr-MIF-1 on [3H]SR 95531 binding in mouse cortical synaptosomal membranes. Neither peptide altered [3H]SR 95531 binding across a wide range of concentrations (10(-12)-10(-6) M). Scatchard analysis indicated no change in either apparent affinity or receptor density at both the high-affinity and low-affinity GABA sites with MIF-1 or Tyr-MIF-1, 10(-9) M. Thus, MIF-1 and Tyr-MIF-1 do not affect binding at the GABA site on the GABAA receptor.

Animals↗

PubMed2004

Influence of macrophage migration inhibitory factor (MIF) on the zinc content and redox state of protein-bound sulphydryl groups in rat sperm: indications for a new role of MIF in sperm maturation.

The function of macrophage migration inhibitory factor (MIF) in sperm maturation was studied by investigating its role in the biochemical maturation of the outer dense fibres. Rat sperm obtained from the caput and cauda epididymis were stimulated overnight with either recombinant MIF or MIF-containing vesicles originating from epididymal fluid at various concentrations. The zinc content of both the sperm and the medium was determined by means of atomic absorption spectrometry. Incubation in both recombinant MIF and vesicular MIF resulted in a statistically significant decrease of the zinc content in stimulated caput sperm of approximately 50%. In parallel, the conditioned media showed a clear increase in the concentration of this trace metal. The effect of MIF was less marked in cauda sperm. In addition, we demonstrated a statistically significant increase of detectable free thiol groups in the sperm mid- and principle piece in isolated rat sperm after stimulation with MIF at concentrations of 25 and 50 ng/ml. Our data suggest that MIF plays an important role in the maturation process of rat sperm during epididymal transit by inducing the elimination of zinc and affecting the amount of free sulphydryl groups in the sperm flagella.

Animals↗

PubMed1998

Reversal of established rat crescentic glomerulonephritis by blockade of macrophage migration inhibitory factor (MIF): potential role of MIF in regulating glucocorticoid production.

Macrophage migration inhibitory factor (MIF) is a potent pro-inflammatory cytokine that also counter-regulates glucocorticoid action. We investigated whether immunoneutralization of MIF could reverse established experimental crescentic glomerulonephritis and if this treatment could modulate endogenous glucocorticoid levels. Accelerated anti-GBM glomerulonephritis was induced in six littermate pairs of rats. Once crescentic disease was established on day 7, one animal in each pair was given a daily injection of neutralizing anti-MIF antibody (Ab) or irrelevant isotype control Ab for 14 days and then killed on day 21. In addition, a group of 6 animals was killed on day 7 of disease without any treatment. Animals receiving the control Ab exhibited a rapidly progressive glomerulonephritis with severe renal injury (proteinuria), loss of renal function (creatinine clearance), anemia, and marked histologic damage (including glomerular crescent formation), compared with animals killed on day 7 without treatment. In contrast, anti-MIF Ab treatment partially reversed the disease by restoring normal renal function and reducing histological damage compared with untreated animals killed on day 7 (p < 0.05). Interestingly, anti-MIF Ab treatment also prevented severe anemia (p < 0.05). Reversal of disease was associated with a significant reduction in leukocyte infiltration and activation and renal interleukin-1 (IL-1) production. Importantly, anti-MIF Ab treatment caused a significant increase in endogenous serum corticosterone levels, which correlated with the reversal of disease parameters. In conclusion, this study has demonstrated that blocking MIF activity can partially reverse established crescentic glomerulonephritis and suggests that MIF operates by both enhancing the cellular immune response and suppressing the endogenous anti-inflammatory glucocorticoid response.

Animals↗

PubMed1979

Studies on guinea-pig macrophage migration inhibitory factor (MIF). II. Purification of MIF after treatment with reducing and denaturing agents.

Treatment of guinea-pig macrophage migration inhibitory factor (MIF) containing culture supernatants with the denaturing agents guanidine hydrochloride (Gu HCl) or urea, in the presence or absence of the reducing agent 2-mercaptoethanol (2-ME), or with sodium dodecyl sulphate (SDS), does not destroy biological activity. Alkylation of reduced MIF preparations results in a considerable decrease or total loss of MIF activity. Treatment of supernatants with the combinations, Gu HCl and 2-ME or urea and 2-ME results in the recovery of MIF activity in association with molecules less than 30,000 in molecular weight (mol. wt). After removal of the agents by dialysis, MIF activity is found associated with molecules larger than 30,000. The reduction in mol. wt is dependent on the presence of 2-ME. When MIF-containing supernatants are treated with urea and SDS and fractionated by preparative polyacrylamide gel electrophoresis (PAGE) in the presence of the same agents, MIF activity is recovered in the mol. wt range of 42,000--80,000. When supernatants are treated with 2-me, in addition to urea and SDS, and preparative PAGE is performed in their presence, MIF activity is found associated with material having a mol. wt of 15,000--18,000. Analytical SDS-PAGE of this fraction reveals two or three closely grouped bands corresponding to the above mol. wt range.

Acrylonitrile↗

PubMedDate not supplied

Structure-activity relationships of analogs of the endogenous brain peptides Tyr-MIF-1 and Tyr-W-MIF-1.

Analogs of the naturally occurring peptides Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2) and Tyr-W-MIF-1 (Tyr-Pro-Trp-GLy-NH2) were synthesized and investigated for their opiate agonist as well as antagonist activity in the guinea pig ileum assay. [Tyr5]-Tyr-MIF-1 and the endogenous Tyr-W-MIF-1 were the most potent opiate agonists among the 20 compounds tested. Several analogs showed antiopiate activity in the ileum from morphine-tolerant animals as measured by attenuation of the agonistic effect of DAMGO, which inhibits electrically stimulated contractions of the ileum. The binding activity of the analogs at mu opiate receptors was determined by displacement of [3H]-DAMGO in rat brain. Tyr-W-MIF-1 and its analogs were more potent than Tyr-MIF-1 and its analogs in this binding assay. Thus, Tyr-MIF-1, Tyr-W-MIF-1 and several of their analogs could act as opiate agonists as well as antagonists.

Amino Acid Sequence↗

PubMed1986

Biphasic effects of MIF-1 and Tyr-MIF-1 on apomorphine-induced stereotypy in rats.

The effects of several doses of MIF-1 and Tyr-MIF-1 (0.2, 0.5, 1.0 and 5.0 mg/kg, SC) on the stereotypic behavior induced by various doses (0.08, 0.2, 0.5, 1.0 and 2.0 mg/kg, SC) of apomorphine (APO) were tested in rats. MIF-1 increased the stereotypic behavior induced by 0.5 and 1.0 mg/kg of APO, but decreased the stereotypic behavior induced by 2.0 mg/kg of APO. Tyr-MIF-1 showed a biphasic effect similar to that exerted by MIF-1. The results suggest that the type of response to MIF-1 and Tyr-MIF-1 after APO is influenced by the activity of central dopaminergic neurons.

Animals↗

PubMed1986

Acute administration of MIF-1 or Tyr-MIF-1 inhibits haloperidol-induced catalepsy in rats.

The effects of MIF-1 (Pro-Leu-Gly-NH2) and Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2) on haloperidol-induced catalepsy were studied in order to examine the influences of both peptides on central dopaminergic function. In the first experiment, several variables were tested. It was found that the optimal effect was achieved with a dose of 1.0 mg/kg haloperidol injected SC an hour before testing for catalepsy and 1.0 mg/kg MIF-1 injected SC 30 min before testing. In the second experiment, Tyr-MIF-1 as well as MIF-1 were injected as single injections at four doses. Catalepsy was inhibited in an inverted U-shape dose-response relationship with the maximal effect of each peptide occurring at 1.0 mg/kg. The results indicate that when careful attention is given to dose, both MIF-1 and Tyr-MIF-1 can activate dopaminergic neuronal activity after acute administration.

Animals↗

PubMed1984

Tyr-MIF-1 and MIF-1 are active in the water wheel test for antidepressant drugs.

MIF-1 [Pro-Leu-Gly-NH2] and Tyr-MIF-1 [Tyr-Pro-Leu-Gly-NH2] were tested in a system in which antidepressant drugs are known to result in increased wheel turning as mice attempt to escape from a small tank of water. One hr after injection, both peptides were found to cause a significant increase of the number of rotations of the wheel at doses as low as 0.01 mg/kg IP, the dose-response pattern for MIF-1 resembling an inverted-U. DSIP and morphine, by contrast, decreased the number of rotations. Under the conditions tested, neither MIF-1 nor Tyr-MIF-1 reversed the effect of morphine. The results demonstrate that MIF-1 and Tyr-MIF-1 are active in another test for antidepressants.

Animals↗

PubMed1977

Synthetic melanocyte stimulating hormone release-inhibiting factor (MIF). Part III: effect of L-prolyl-N-methyl-D-leucyl-glycinamide and MIF on biogenic amine turnover.

The effect of the factor that inhibits the release of melanocyte stimulating hormone (MSH), i.e., L-prolyl-L-leucyl-glycinamide (MIF), and L-prolyl-N-methyl-D-leucyl-glycinamide, an analog, on brain norepinephrine (NE), dopamine (DA) and serotonin (5-HT) turnover was examined in rats. The analog (40 mg/kg i.p.), in a fashion similar to MIF (40 and 5 mg/kg i.p.), increased brain DA turnover; only MIF (40 mg/kg i.p.) increased endogenous DA levels. The analog (40 and 5 mg/kg i.p.) decreased brain NE turnover; MIF at the same doses was ineffective. Neither MIF nor the analog affected rat brain 5-HT turnover or the 5-HTP-induced behavioural syndrome in the mouse. These results indicate that the analog, like MIF, exerts effects on central catecholamine turnover. The different biochemical profile of the analog compared to MIF may be importance with regard to potential clinical use in the treatment of Parkinson's disease and depression.

5-Hydroxytryptophan↗

PubMed1988

Structural specificity of MIF-1 and Tyr-MIF-1 in augmenting GABA-stimulated benzodiazepine receptor binding.

The possibility of a linkage between endogenous peptides and the GABA-benzodiazepine system has been greatly strengthened by reports that the brain peptides MIF-1(Pro-Leu-Gly-NH2) and Tyr-MIF-1(Tyr-Pro-Leu-Gly-NH2) augment GABA-stimulated benzodiazepine binding. We evaluated the actions of fragments and analogs of these small peptides on GABA-stimulated benzodiazepine binding in mouse cortical brain membranes. Fragments of Tyr-MIF-1, several compounds related to MIF-1, or several analogs of Tyr-MIF-1 had no effect on binding. These results demonstrate the specificity of the effects of MIF-1 and Tyr-MIF-1 on GABA-stimulated benzodiazepine binding.

Animals↗

PubMed1988

Blockade of brain dopamine receptors antagonizes the anti-immobility effect of MIF-1 and Tyr-MIF-1 in rats.

Previous studies have shown effects of MIF-1 (prolyl-leucyl-glycinamide) and Tyr-MIF-1 (tyrosyl-prolyl-leucyl-glycinamide) in animal models of depression and also effects on dopaminergic function. These observations prompted us to examine whether the effects of the two peptides in the behavioral 'despair' test were modulated by dopamine antagonists. MIF-1 and Tyr-MIF-1, at the small dose of 0.01 mg/kg i.p. (24, 5 and 1 h before the test), produced a significant anti-immobility effect. This effect was antagonized by a single injection of either haloperidol or sulpiride, two dopamine receptor blockers. The same low dose of the tricyclic antidepressant desipramine was without significant effect in this test. The results indicate that Tyr-MIF-1, like MIF-1, is active in the behavioral despair test for antidepressants and that at least some of the CNS actions of these peptides are mediated by dopamine receptors.

Animals↗

PubMed1989

MIF-1 and Tyr-MIF-1 fail to alter benzodiazepine-induced hypothermia.

Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2) and MIF-1 (Pro-Leu-Gly-NH2) can increase GABA-stimulated benzodiazepine binding in brain tissue can block the hypothermia induced by several other compounds. Since benzodiazepines can also cause hypothermia, colonic temperatures were measured in mice after administration of chlordiazepoxide (CDP) and these two brain peptides. In several experiments involving different doses and times of administration of CDP, MIF-1, and Tyr-MIF-1, there were no significant effects of the peptides in altering the reliable decrease in colonic temperature induced by the benzodiazepine. The results indicate that the interaction of Tyr-MIF-1 and MIF-1 with benzodiazepines does not involve thermoregulation.

Animals↗

PubMedDate not supplied

MIF-1 and Tyr-MIF-1 augment GABA-stimulated benzodiazepine receptor binding.

Behavioral evidence in laboratory animals and human beings indicates possible links between the endogenous opiate and gamma-aminobutyric acid (GABA)-benzodiazepine receptor systems, especially with regard to antagonistic properties. To assess possible interactions between endogenous opiate antagonists and benzodiazepine receptor binding, we evaluated the effects of the peptides MIF-1 and Tyr-MIF-1 on benzodiazepine receptor binding in mouse brain membranes. Neither peptide affected receptor binding in cortex over a broad dose range, but both peptides significantly augmented GABA-stimulated benzodiazepine receptor binding at GABA concentrations of 10(-8) and 10(-7) M. Rosenthal-Scatchard analysis indicated that the increase in binding was largely due to increased apparent affinity. Both peptides augmented GABA-enhanced binding at low doses (MIF-1 10(-11) M, Tyr-MIF-1 10(-13) M) with decreased effects at higher doses. In cerebellum and brainstem, MIF-1 tended to enhance GABA-stimulated binding but Tyr-MIF-1 was inactive. These results indicate benzodiazepine-opiate and benzodiazepine-peptide interactions.

Animals↗

PubMedDate not supplied

MIF-1 and Tyr-MIF-1 antagonize morphine and opioid but not non-opioid stress-induced analgesia in the snail, Cepaea nemoralis.

The effects of prolyl-leucyl-glycinamide (MIF-1, PLG), tyrosine-prolyl-leucyl-glycinamide (Tyr-MIF-1, YPLG) and naloxone on morphine and warm and cold stress-induced increases in the latency of the thermal (40 degrees C hot plate) avoidance behaviors of the terrestrial snail, Cepaea nemoralis, were examined. All three substances blocked the morphine- and warm stress-induced opioid analgesia, while having no effects on non-opioid cold stress-induced analgesia. Tyr-MIF-1 had a significantly greater inhibitory effect than MIF-1. These results indicate that MIF-1 and Tyr-MIF-1 antagonize the antinociceptive effects of exogenous opiates and opioid-mediated analgesia in snails in a manner analogous to that described for mammals. This raises the possibility of an evolutionary conservation of functional opioid antagonists.

Animals↗