Biomedical subjects

Linda Lundström

Publications and source records attributed to Linda Lundström.

11 recordsLinked to original sources

PubMed2006

Activation of peripheral galanin receptors: differential effects on nociception.

Numerous reports suggest a significant role of peripheral galanin (GAL) in pain transmission; however, due to the lack of selective galanin receptor agonists and antagonists, the role of GAL receptors (GalR1-3) in pain transmission remains unclear. In this study, a new agonist, M617, that preferentially binds to GalR1, a GalR2 agonist (AR-M1896), and a GalR2 antagonist (M871) were tested in the periphery to elucidate the role of peripheral GalR1 and GalR2 in nociception. Ipsilateral, but not contralateral, hindpaw injection of M617 reduced capsaicin (CAP)-induced flinching by approximately 50%, suggesting that GalR1 activation produces anti-nociception. This anti-nociceptive effect was blocked by intraplantar injection of the non-selective GalR antagonist M35. In contrast ipsilateral, but not contralateral, intraplantar injection of GalR2 agonist AR-M1896 enhanced the CAP-induced nociception (1.7-fold). The GalR2 antagonist M871 blocked the pro-nociceptive effect of AR-M1896 in a dose-dependent manner. This antagonist had no effect on nociceptive behaviors induced by CAP alone. The data demonstrate that activation of peripheral GalR1 results in anti-nociception but activation of peripheral GalR2 produces pro-nociception. Thus, the use of these pharmacological tools may help to elucidate the contribution of GalR subtypes in nociceptive processing, identifying potential drug targets for the treatment of peripheral pain.

Animals↗

PubMed2006

Regulation of kindling epileptogenesis by hippocampal galanin type 1 and type 2 receptors: The effects of subtype-selective agonists and the role of G-protein-mediated signaling.

The search for antiepileptic drugs that are capable of blocking the progression of epilepsy (epileptogenesis) is an important problem of translational epilepsy research. The neuropeptide galanin effectively suppresses acute seizures. We examined the ability of hippocampal galanin receptor type 1 (GalR1) and type 2 (GalR2) to inhibit kindling epileptogenesis and studied signaling cascades that mediate their effects. Wistar rats received 24-h-long intrahippocampal infusion of a GalR1/2 agonist galanin(1-29), GalR1 agonist M617 [galanin(1-13)-Gln14-bradykinin(2-9)-amide], or GalR2 agonist galanin(2-11). The peptides were administered alone or combined with an inhibitor of Gi protein pertussis toxin (PTX), Gi-protein activated K+ channels (GIRK) inhibitor tertiapin Q (TPQ), G(q/11) protein inhibitor [D-Arg1,D-Trp(5,7,9),Leu11]-substance P (dSP), or an inhibitor of intracellular Ca2+ release dantrolene. Sixteen hours into drug delivery, the animals were subjected to rapid kindling-60 electrical trains administered to ventral hippocampus every 5 min. M617 delayed epileptogenesis, whereas galanin(1-29) and galanin(2-11) completely prevented the occurrence of full kindled seizures. TPQ abolished anticonvulsant effect of M617 but not of galanin(2-11). PTX blocked anticonvulsant effects of M617 and inversed the action of galanin(1-29) and galanin(2-11) to proconvulsant. dSP and dantrolene did not modify seizure suppression through GalR1 and GalR2, but eliminated the proconvulsant effect of PTX + galanin(1-29) and PTX + galanin(2-11) combinations. We conclude that hippocampal GalR1 exert their disease-modifying effect through the Gi-GIRK pathway. GalR2 is antiepileptogenic through the Gi mechanism independent of GIRK. A secondary proconvulsant pathway coupled to GalR2 involves G(q/11) and intracellular Ca2+. The data are important for understanding endogenous mechanisms regulating epileptogenesis and for the development of novel antiepileptogenic drugs.

Animals↗

PubMed2005

Multiple interaction sites of galnon trigger its biological effects.

Galnon was first reported as a low molecular weight non-peptide agonist at galanin receptors [Saar et al. (2002) Proc. Natl. Acad. Sci. USA 99, 7136-7141]. Following its systemic administration, this synthetic ligand affected a range of important physiological processes including appetite, seizures and pain. Physiological activity of galnon could not be explained solely by the activation of the three known galanin receptors, GalR1, GalR2 and GalR3. Consequently, it was possible that galnon generates its manifold effects by interacting with other signaling pathway components, in addition to via GalR1-3. In this report, we establish that galnon: (i) can penetrate across the plasma membrane of cells, (ii) can activate intracellular G-proteins directly independent of receptor activation thereby triggering downstream signaling, (iii) demonstrates selectivity for different G-proteins, and (iiii) is a ligand to other G-protein coupled receptors (GPCRs) in addition to via GalR1-3. We conclude that galnon has multiple sites of interaction within the GPCR signaling cascade which mediate its physiological effects.

Animals↗

PubMed2005

Important pharmacophores for binding to galanin receptor 2.

Galanin(2-11) has been introduced as a receptor subtype selective ligand for the GalR2 subtype of the galanin receptors, and has gained use in pharmacological studies of galaninergic signaling in the past two years. By introducing l-Ala substitutions in the galanin(2-11) sequence, we have examined the amino acid residues which are of importance for binding to the GalR2 receptor. Our study shows that Trp2, Asn5, Gly8 and Tyr9 are of great importance for high affinity binding. When placed in an alpha-helical conformation, the side chains of these residues are, with the exception of Tyr9, displayed on the same "side" of the peptide. This information is useful in the rational design of non-peptide type GalR2 receptor ligands.

Amino Acid Substitution↗

PubMed2005

Galanin receptor ligands.

The three galanin receptor subtypes (GalR1-3) belong to the G protein-coupled receptor superfamily. The widespread distribution of galanin and its receptors in the CNS and PNS and the numerous physiological and pharmacological effects of galanin (for review, cf. Vrontakis, 2002) render the three galanin receptors attractive drug targets. The industrial efforts, however, have not yet resulted in a wealth of receptor subtype specific agonists or antagonists with high affinity and selectivity. The present paper summarizes the properties of the galanin ligands used at the end of 2004 in the ca. 2000 publications and complements their pharmacological characterization with new data.

Animals↗

PubMed2005

Galanin (2-11) binds to GalR3 in transfected cell lines: limitations for pharmacological definition of receptor subtypes.

The neuropeptide galanin regulates a variety of physiological and pathophysiological processes through three G protein coupled receptors, GalR1, GalR2, and GalR3. The studies on galanin receptor subtype specific effects have been hampered by the lack of high affinity subtype selective antagonist and/or agonist to any of these three galanin receptor subtypes. Since its recent introduction in 2003, galanin (2-11) has been widely used as a GalR2 selective agonist in several in vitro and in vivo studies. In the present paper, we demonstrate that galanin (2-11) binds to rat GalR3 receptors in transfected cell lines with a similar affinity as it binds to GalR2. As none of the available antagonists are galanin receptor subtype selective, as shown here for M35 and M40, more work is needed to confirm whether a galanin (2-11) effect is GalR2 mediated and there is an urgent need for high affinity galanin receptor subtype selective ligands. For now one needs to interpret the data obtained at lower galanin (2-11) concentrations as effects mediated by non-GalR1 type galanin receptors, i.e., GalR2 and/or GalR3.

Animals↗

PubMed2005

Assessment of objective and subjective eccentric refraction.

PURPOSE: When performing perimetry, refracting subjects with central visual field loss, and in emmetropization studies, it is important to accurately measure peripheral refractive errors. Traditional methods for foveal refraction often give uncertain results in eccentric angles as a result of the large aberrations and the reduced retinal function. The aim of this study is therefore to compare and evaluate four methods for eccentric refraction. METHODS: Four eccentric methods were tested on 50 healthy subjects: one novel subjective procedure, optimizing the detection contrast sensitivity with different trial lenses, and three objective ones: photorefraction with a PowerRefractor, wavefront measurements with a Hartmann-Shack sensor, and retinoscopy. The peripheral refractive error in the horizontal nasal visual field of the right eye was measured in 20 degrees and 30 degrees. RESULTS: In general, the eccentric refraction methods compared reasonably well. However, the following differences were noted. Retinoscopy showed a significant difference from the other methods in the axis of astigmatism. In 30 degree eccentric angle, it was not possible to measure 15 of the subjects with the PowerRefractor and the instrument also tended to underestimate high myopia (<-6 D). The Hartmann-Shack sensor showed a myopic shift of approximately 0.5 D in both eccentricities. The subjective method had a relatively larger spread. CONCLUSIONS: This study indicates that it is possible to assess the eccentric refraction with all methods. However, the Hartmann-Shack technique was found to be the most useful method. The agreement between the objective methods and the subjective eccentric refraction shows that detection contrast sensitivity in the periphery is affected by relatively small amounts of defocus.

Adult↗

PubMed2005

Galanin and its receptors in neurological disorders.

Galanin is a highly inducible neuropeptide, showing distinct up-regulation after pathological disturbance within the nervous system. Significant increase in galanin expression is observed after peripheral nerve injury, in the basal forebrain in Alzheimer's disease (AD), during neuronal development, and after stimulation with estrogen, while seizure activity deplete galanin in the hippocampus. A wide distribution of galanin and its receptors is seen in the nervous system, often in co-localization with classical neurotransmitters and other neuromodulators. Galanin acts predominantly as an inhibitory, hyperpolarizing neuromodulator on neurotransmitter and glucose-induced insulin release and stimulates growth hormone and prolactin secretion. Galanin has been implicated in several higher order physiological functions including cognition, feeding, nociception, mood regulation, and neuroendocrine modulation. The effects of galanin are mediated via three G protein-coupled receptors with different functional coupling. Moderate to low pharmacological effects are seen by galanin under physiological conditions, in contrast to its dramatic effects on the nervous system after neuronal disturbance. This pathophysiological heavy function of the galaninergic system renders it an interest for disorders such as AD, depression, and epilepsy in terms of side effects. Some properties of the galaninergic system are of particular importance in the context of neurodegeneration. Galanin is highly inducible, 10- to 100-fold, upon nerve injury, whereas most neuropeptides are induced 1.5- to 2-fold. Galanin is strongly neurotrophic during development as well as subsequent to injury. Whereas other neurotrophic neuropeptides like VIP and PACAP activate cAMP synthesis, galanin suppresses its synthesis, yet it is a strong neurotrophic as well as neuroprotective agent. As we delineate which galanin receptor subtype mediates neuroprotective and neurotrophic effects and which mediates synaptic inhibition, pharmacological use of receptor- selective galaninergic ligands for treatment in neurodegenerative diseases are coming closer.

Animals↗

PubMed2004

Unwrapping Hartmann-Shack images from highly aberrated eyes using an iterative B-spline based extrapolation method.

PURPOSE: When the wavefront aberrations of the eye are measured with a Hartmann-Shack (HS) sensor, the resulting spot pattern must be unwrapped, that is, for each lenslet the corresponding spot must be identified. This puts a limitation on the measurable amount of aberrations. To extend the range of an HS sensor, a powerful unwrapping algorithm has been developed. METHODS: The unwrapping algorithm starts by connecting the central HS spots to the central lenslets. It then fits a B-spline function through a least squares estimate to the deviations of the central HS spots. This function is then extrapolated to find the expected locations of HS spots for the unconnected lenslets. The extrapolation is performed gradually in an iterative manner; the closest unconnected lenslets are extrapolated and connected, and then the B-spline function is least squares fitted to all connected HS spots and extrapolated again. RESULTS: Wavefront aberrations from eyes with high aberrations can be successfully unwrapped with the developed algorithm. The dynamic range of a typical HS sensor increases 3.5 to 13 times compared with a simple unwrapping algorithm. CONCLUSIONS: The implemented algorithm is an efficient unwrapping tool and allows the use of lenslets with a low numerical aperture and thus gives a relatively higher accuracy of measurements of the ocular aberrations.

Algorithms↗

PubMed2003

Systemic galnon, a low-molecular weight galanin receptor agonist, reduces heat hyperalgesia in rats with nerve injury.

We have examined the effect of systemically administered galnon, a novel low-molecular weight agonist of galanin receptors, on neuropathic pain-like behaviors in rats after photochemically induced partial nerve injury. Galnon is a galanin receptor ligand with moderate affinity to spinal cord membranes (K(D) of 6+/-0.6 microM). While intraperitoneally applied galnon produced no significant effect on mechanical or cold hypersensitivity, it dose-dependently prolonged heat withdrawal latency in nerve-injured rats. The effect of galnon was more potent on the injured side which has significantly shorter latency than the contralateral side. The anti-hyperalgesic effect of galanon was prevented by intrathecal M35, a galanin receptor antagonist. No side effects, such as sedation or motor impairment, were seen following systemic galnon treatment at the doses used. It is concluded that systemic galnon alleviated heat-hyperalgesic response in rats with partial sciatic nerve injury. This effect was likely to be mediated by activation of spinal galanin receptors.

Animals↗

PubMedDate not supplied

Off-axis wave front measurements for optical correction in eccentric viewing.

In a previous study we have shown that correction of peripheral refractive errors can improve the remaining vision of subjects with large central visual field loss. Measuring peripheral refractive errors with traditional methods is often difficult due to low visual acuity and large aberrations. Therefore a Hartmann-Shack sensor has been designed to measure peripheral wave front aberrations in subjects using eccentric viewing. The sensor incorporates an eye tracker and analyzing software designed to handle large wave front aberrations and elliptic pupils. To ensure that the measurement axis is aligned with the direction of the subject's preferred retinal location, a special fixation target has been developed. It consists of concentric rings surrounding the aperture of the sensor together with a central fixation mark along the measurement axis. Some initial measurements on subjects using eccentric viewing have been performed successfully. As a first step in improving the peripheral optics of the eye, the wave front has been used to calculate the eccentric refraction. This refraction has been compared to the refraction found with the PowerRefractor instrument. Measuring the off-axis wave front is a fast way to assess the optical errors in the subject's eccentric viewing angle and to better understand the problems of eccentric correction.

Equipment Design↗