Laszlo Hackler
Tulane University
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Featured researches published by Laszlo Hackler.
Peptides | 1997
Laszlo Hackler; James E. Zadina; Lin-Jun Ge; Abba J. Kastin
Endomorphin-1 (Tyr-Pro-Trp-Phe-NH2) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH2) were previously isolated from bovine brain. Both peptides showed the greatest selectivity and affinity for the mu opiate receptor of any endogenous substance found to date and may serve as natural ligands for the mu-opiate receptor. We have purified them from the fronto-parietal cortex of human brain tissue by solid phase extraction and high performance liquid chromatography. Peptide content was followed by a specific and sensitive radioimmunoassay with an antibody that was generated against endomorphin-1. The isolated endomorphins showed full biological activity. The tetrapeptides were found in human brain in much higher amounts than in bovine frontal cortex.
Annals of the New York Academy of Sciences | 1999
James E. Zadina; Sheryl Martin-Schild; Arnold A. Gerall; Abba J. Kastin; Laszlo Hackler; Lin-Jun Ge; Xing Zhang
Abstract: Endomorphin‐1 (Tyr‐Pro‐Trp‐Phe‐NH2, EM‐1) and endomorphin‐2 (Tyr‐Pro‐Phe‐Phe‐NH2, EM‐2) are peptides recently isolated from brain that show the highest affinity and selectivity for the m (morphine) opiate receptor of all the known endogenous opioids. The endomorphins have potent analgesic and gastrointestinal effects. At the cellular level, they activate G‐proteins (35S‐GTP γ‐S binding) and inhibit calcium currents. Support for their role as endogenous ligands for the μ‐opiate receptor includes their localization by radioimmunoassay and immunocytochemistry in central nervous system regions of high μ receptor density. Intense EM‐2 immunoreactivity is present in the terminal regions of primary afferent neurons in the dorsal horn of the spinal cord and in the medulla near high densities of μ receptors. Chemical (capsaicin) and surgical (rhizotomy) disruption of nociceptive primary afferent neurons depletes the immunoreactivity, implicating the primary afferents as the source of EM‐2. Thus, EM‐2 is well‐positioned to serve as an endogenous modulator of pain in its earliest stages of perception. In contrast to EM‐2, which is more prevalent in the spinal cord and lower brainstem, EM‐1 is more widely and densely distributed throughout the brain than EM‐2. The distribution is consistent with a role for the peptides in the modulation of diverse functions, including autonomic, neuroendocrine, and reward functions as well as modulation of responses to pain and stress.
Peptides | 1997
Hunter C. Champion; James E. Zadina; Abba J. Kastin; Laszlo Hackler; Lin-Jun Ge; Philip J. Kadowitz
Endomorphin 1 and 2 are recently discovered endogenous ligands for the mu-opioid receptor. In the present study, responses to intravenous administration of endomorphin 1 and 2 were investigated in the systemic vascular bed of the rat. Endomorphin 1 and 2 induced dose-related decreases in systemic arterial pressure when injected in doses of 10-100 nmol/kg i.v.. The decreases in systemic arterial pressure in response to endomorphin 1 and 2 were associated with significant decreases in heart rate, cardiac output, and total peripheral resistance. The endogenous ligand for the ORL1 receptor, nociceptin/OFQ had similar effects on systemic arterial pressure, heart rate, cardiac output, and total peripheral resistance in the rat. Injections of isoproterenol (1 microgram/kg i.v.) and calcitonin gene-related peptide (CGRP; 0.3 nmol/kg i.v.), decreased systemic arterial pressure and total peripheral resistance. However these decreases in arterial pressure were associated with increases in heart rate and cardiac output. The results of the present study demonstrate that the endomorphin peptides have significant vasodilator activity in the systemic vascular bed of the rat and show that this response is associated with a decrease in heart rate and cardiac output.
Life Sciences | 1994
James E. Zadina; Abba J. Kastin; Lin-Jun Ge; Laszlo Hackler
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.
Life Sciences | 1998
Marc A. Czapla; Hunter C. Champion; James E. Zadina; Abba J. Kastin; Laszlo Hackler; Lin-Jun Ge; Philip J. Kadowitz
The endogenous opioid peptides, endomorphin 1 and 2, are newly isolated, potent, and selective mu-opioid receptor agonists. In the present study, responses to endomorphin 1 and 2 were investigated in the systemic vascular bed of the rat. Endomorphin 1 and 2 induced dose-related decreases in systemic arterial pressure when injected in doses of 1-30 nmol/kg i.v. In terms of relative vasodepressor activity, endomorphin 1 and 2 were approximately equipotent with each other and with the ORL1 ligand, nociceptin (orphanin FQ), and were about 10-fold more potent than met-enkephalin in decreasing systemic arterial pressure. Vasodepressor responses to endomorphin 1 and 2 and met-enkephalin, but not to nociceptin, were inhibited by the opioid receptor antagonist, naloxone. These results demonstrate that endomorphin 1 and 2 produce significant naloxone-sensitive decreases in systemic arterial pressure.
Neuroendocrinology | 2001
Abba J. Kastin; Victoria Akerstrom; Laszlo Hackler
Galanin-like peptide (GALP) was recently isolated from the hypothalamus, where its expression is influenced by leptin and food deprivation. Since leptin crosses the blood-brain barrier (BBB) by a saturable transport system that is downregulated by fasting, we examined the effect of leptin and fasting on the entry of GALP into mouse brain. Multiple-time regression analysis showed that the basal influx of 125I-GALP from blood was rapid (Ki = 9.49 ± 0.72 × 10–4 ml/g·min). This influx was not affected by leptin but was significantly decreased by food deprivation for 24 or 48 h, accompanied by decreased immunoreactive plasma GALP at 48 h, but not at 24 h. By contrast, pretreatment of mice fasted for 24 h with glucose resulted in a significant increase in the blood-to-brain influx of GALP that was not accompanied by increased immunoreactive plasma GALP. HPLC showed that most of the GALP crossed the BBB in an intact form, and capillary depletion studies showed that more than 93% of the GALP crossing entered the parenchyma of the brain rather than being bound to the endothelial cells of the capillaries composing the BBB or being reversibly associated with the vasculature. Efflux of 125I-GALP occurred at the rate of the normal reabsorption of CSF, and the octanol-buffer partition coefficient showed insufficient lipophilicity to explain the fast rate of influx. When 125I-GALP was perfused in blood-free buffer, the self-inhibition characteristic of a saturable transport system was evident even though capillary gel electrophoresis showed GALP aggregating as a trimer. Capillary zone electrophoresis showed protein binding of GALP in serum, perhaps facilitating its interactions at the BBB. In particular, these studies show for the first time (1) that immunoreactive GALP is present in blood where (2) its concentrations are reduced by food deprivation, and (3) that there is a rapid blood-to-brain influx of intact GALP (4) which is decreased by fasting and (5) increased by pretreatment with glucose.
Journal of Neurochemistry | 2001
Abba J. Kastin; Victoria Akerstrom; Laszlo Hackler; James E. Zadina
Abstract: Melanin‐concentrating hormone (MCH), found both peripherally and centrally, is involved in food ingestion. Although its expression in brain is increased by fasting, it is not known whether it crosses the bloodbrain barrier (BBB). Use of the sensitive method of multiple‐time regression analysis has shown that almost all of the peptides and polypeptides tested cross the BBB at a rate faster than the vascular marker albumin. With this same method, however, we found that the 19‐amino acid 125I‐Phe13, Tyr19‐MCH did not cross faster than 99mTc‐albumin. Several mechanisms were excluded as possible explanations for the slow rate of influx. These included degradation, association with capillary endothelial cells, and transport from brain to blood. When Phe13, Tyr19‐MCH was perfused in blood‐free buffer, however, it entered the brain significantly faster than albumin. This suggested protein binding as an explanation for the slow rate of influx when the MCH was administered in blood. Protein binding was confirmed by capillary zone electrophoresis, which showed that almost all of the Phe13, Tyr19‐MCH added to blood migrated with a large‐molecular‐weight substance. Sodium dodecyl sulfate—capillary gel electrophoresis of Phe13, Tyr19‐MCH in buffer additionally showed that the MCH aggregated as a trimer, a factor not preventing its influx by blood‐free perfusion. Thus, the results show that blood‐borne Phe13, Tyr19‐MCH does not significantly cross the BBB, probably because of its binding to serum proteins.
Neuropeptides | 1993
Laszlo Hackler; Abba J. Kastin; Judit Erchegyi; James E. Zadina
Tyr-W-MIF-1 (Tyr-Pro-Trp-Gly-NH2) was recently isolated from human brain cortex. We have now isolated it from bovine hypothalami by solid phase extraction and several consecutive rpHPLC steps monitored by an RIA originally developed for the endogenous brain peptide Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2). Determination of the sequence of the purified material and comparison of its chromatographic behavior with synthetic Tyr-W-MIF-1 confirmed the structure. The synthetic peptide and the isolated material showed almost identical binding to mu opiate receptors.
Peptides | 2002
Abba J. Kastin; Weihong Pan; Victoria Akerstrom; Laszlo Hackler; Chuanfeng Wang; Catherine M. Kotz
There is need for a new approach to the suppression of feeding. Here, we show that two of the most potent endogenous satiety peptides interact in a novel way to cross the blood-brain barrier (BBB) and to suppress food intake. Combined peripheral administration of leptin and urocortin (UCN) significantly decreased food intake, whereas neither one showed an effect when given alone in the same doses. We further provide a mechanism whereby this novel cooperativity can occur by demonstrating that UCN, which by itself does not cross the BBB, can readily enter the brain by associating with leptin. Such a novel interaction between two peptides at the BBB opens new approaches for general study of the dynamic regulatory role of the BBB in brain-body communication as well as the specific study of obesity.
Neuroscience Letters | 1993
James E. Zadina; Abba J. Kastin; Velga Kenigs; Carlos Bruno; Laszlo Hackler
A peptide recently isolated from human and bovine brain, Tyr-W-MIF-1 (Tyr-Pro-Trp-Gly-NH2), was tested for its effects on nociception in the tail-flick test after intracerebroventricular injection in the rat. Tail-flick latencies were significantly increased with a rapid onset and remained significantly elevated for at least 50 min. Naloxone reversed the effect of the peptide, indicating opiate receptor involvement in the response. Met-enkephalin at the same dose produced only slight antinociception. Some animals showed barrel-rolling behavior in addition to the analgesia; this behavior was unusually short-lived, not a prerequisite for the analgesia, and had no apparent persistent effects. The results show that, in addition to previously described opiate-like actions (binding to the mu-receptor and inhibition of electrically induced contractions of the guinea pig ileum), Tyr-W-MIF-1 is capable of inducing significant analgesia.