Mainz, Germany

Time filter

Source Type

Takata K.,Kyoto Pharmaceutical University | Kitamura Y.,Kyoto Pharmaceutical University | Saeki M.,Kyoto Pharmaceutical University | Terada M.,Kyoto Pharmaceutical University | And 7 more authors.
Journal of Biological Chemistry | Year: 2010

Reduction of brain amyloid-β (Aβ) has been proposed as a therapeutic target for Alzheimer disease (AD), and microglial Aβ phagocytosis is noted as an Aβ clearance system in brains. Galantamine is an acetylcholinesterase inhibitor approved for symptomatic treatment of AD. Galantamine also acts as an allosterically potentiating ligand (APL) for nicotinic acetylcholine receptors (nAChRs). APL-binding site is located close to but distinct from that for acetylcholine on nAChRs, and FK1 antibody specifically binds to the APL-binding site without interfering with the acetylcholine-binding site. We found that in human AD brain, microglia accumulated on Aβ deposits and expressed α7 nAChRs including the APL-binding site recognized with FK1 antibody. Treatment of rat microglia with galantamine significantly enhanced microglial Aβ phagocytosis, and acetylcholine competitive antagonists as well as FK1 antibody inhibited the enhancement. Thus, the galantamine-enhanced microglial Aβ phagocytosis required the combined actions of an acetylcholine competitive agonist and the APL for nAChRs. Indeed, depletion of choline, an acetylcholine-competitive α7 nAChR agonist, from the culture medium impeded the enhancement. Similarly, Ca2+ depletion or inhibition of the calmodulin-dependent pathways for the actin reorganization abolished the enhancement. These results suggest that galantamine sensitizes microglial α7 nAChRs to choline and induces Ca2+ influx into microglia. The Ca2+-induced intracellular signaling cascades may then stimulate Aβ phagocytosis through the actin reorganization. We further demonstrated that galantamine treatment facilitated Aβ clearance in brains of rodent AD models. In conclusion, we propose a further advantage of galantamine in clinical AD treatment and microglial nAChRs as a new therapeutic target. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.


Ludwig J.,Galantos Pharma | Hoffle-Maas A.,Galantos Pharma | Samochocki M.,Galantos Pharma | Luttmann E.,University of Paderborn | And 4 more authors.
Journal of Receptors and Signal Transduction | Year: 2010

Galantamine is an approved drug treatment for Alzheimer's disease. Initially identified as a weak cholinesterase inhibitor, we have established that galantamine mainly acts as an 'allosterically potentiating ligand (APL)' of nicotinic acetylcholine receptors (nAChR). Meanwhile other 'positive allosteric modulators (PAM)' of nAChR channel activity have been discovered, and for one of them a binding site within the transmembrane domain has been proposed. Here we show, by performing site-directed mutagenesis studies of ectopically expressed chimeric chicken α7/mouse 5-hydroxytryptamine 3 receptor-channel complex, in combination with whole-cell current measurements, in the presence and absence of galantamine, that the APL binding site is different from the proposed PAM binding site. We demonstrate that residues T197, I196, and F198 of ß-strand 10 represent major elements of the galantamine binding site. Residue K123, earlier suggested as being 'close to' the APL binding site, is not part of this site but rather appears to play a role in coupling of agonist binding to channel opening and closing. Our data confirm our earlier results that the galantamine binding site is different from the ACh binding site. Both sites are in close proximity and hence may influence each other in a synergistic fashion. Other interesting areas identified in the present study are a 'hinge' region around and containing residues F122, K123, and K143 possibly being involved in relaying the signal of agonist binding to gating of the transmembrane channel, and a 'folding centre', with P119 as the dominating residue, that crucially positions the agonist binding site with respect to the hinge region. © 2010 Informa Healthcare USA, Inc.


Bhattacharya S.,Leibniz Institute for Neurobiology | Haertel C.,Leibniz Institute for Neurobiology | Maelicke A.,Galantos Pharma | Montag D.,Leibniz Institute for Neurobiology
PLoS ONE | Year: 2014

The plant alkaloid galantamine is an established symptomatic drug treatment for Alzheimer's disease (AD), providing temporary cognitive and global relief in human patients. In this study, the 5X Familial Alzheimer's Disease (5XFAD) mouse model was used to investigate the effect of chronic galantamine treatment on behavior and amyloid β (Aβ) plaque deposition in the mouse brain. Quantification of plaques in untreated 5XFAD mice showed a gender specific phenotype; the plaque density increased steadily reaching saturation in males after 10 months of age, whereas in females the density further increased until after 14 months of age. Moreover, females consistently displayed a higher plaque density in comparison to males of the same age. Chronic oral treatment with galantamine resulted in improved performance in behavioral tests, such as open field and light-dark avoidance, already at mildly affected stages compared to untreated controls. Treated animals of both sexes showed significantly lower plaque density in the brain, i.e., the entorhinal cortex and hippocampus, gliosis being always positively correlated to plaque load. A high dose treatment with a daily uptake of 26 mg/kg body weight was tolerated well and produced significantly larger positive effects than a lower dose treatment (14 mg/kg body weight) in terms of plaque density and behavior. These results strongly support that galantamine, in addition to improving cognitive and behavioral symptoms in AD, may have disease-modifying and neuroprotective properties, as is indicated by delayed Aβ plaque formation and reduced gliosis. © 2014 Bhattacharya et al.


Bhattacharya S.,Leibniz Institute for Neurobiology | Maelicke A.,Galantos Pharma | Montag D.,Leibniz Institute for Neurobiology
Journal of Alzheimer's Disease | Year: 2015

The plant alkaloid galantamine is an established symptomatic drug treatment for Alzheimer's disease (AD), providing cognitive and global relief in human patients. However, as an acetylcholinesterase inhibitor, gastrointestinal side effects limit the dosage and duration of treatment. Memogain (Gln-1062), a pro-drug, liberates galantamine on cleavage by a carboxyesterase in the brain. The possibility to deliver Memogain intranasally may further circumvent side effects, allowing higher dosing compared to galantamine. In this study, the 5X Familial Alzheimer's Disease (5XFAD) mouse model was used to investigate the effect of chronic Memogain treatment on behavior and amyloid-′ (A′) plaque deposition in the brain. Chronic intranasal dosage of 6 mg/kg body weight twice daily was tolerated well, whereas the double dose caused body weight loss in males and was less effective in some behavioral tests. 8 weeks of chronic treatment resulted in improved performance in behavioral tests, such as open field and light-dark avoidance, and in fear conditioning already at mildly affected stages at the age of 18 weeks compared to untreated controls. Furthermore, after treatment a significantly lower plaque density in the brain, i.e., in the entorhinal cortex (reduction 20% females, 40% males) and the hippocampus (19% females, 31% males) at the age of 18 weeks was observed. These results show that nasal application of Memogain effectively delivers the drug to the brain with the potential to retard plaque deposition and improve behavioral symptoms in AD similar to the approved galantamine. © 2015 - IOS Press and the authors. All rights reserved.


Galantos Pharma | Entity website

GalantosPharma was founded in 2005 with the aim of satisfying the urgent medical need in Alzheimers disease (AD) for drugs combining both, efficient cognition enhancement and slowing down of disease progression. Rather than joining the band of companies that tried immunotherapeutic or other approaches aimed at removing excessive or misfolded extracellular -amyloid, our program started out from nature-derived compounds, such as the plant alkaloid and marketed AD drug galantamine (Reminyl, Razadyne), and aimed at improving crucial properties of these multi-mode leads ...


The present invention refers to compounds that, in addition to enhancing the sensitivity to acetylcholine and choline, and their exogenous agonists, of neuronal cholinergic receptors and/or acting as cholinesterase inhibitors and/or neuroprotective agents, have enhanced blood-brain barrier permeability in comparison to their parent compounds. The compounds are derived (either formally by their chemical structure or directly by chemical synthesis) from natural compounds belonging to the class of amaryllidaceae alkaloids e.g., galantamine, narwedine and lycoramine, or from metabolites of said compounds. The compounds of the present invention can either interact as such with their target molecules, or they can act as pro-drugs, in the sense that after reaching their target regions in the body they are converted by hydrolysis or enzymatic attack to the original parent compound and react as such with their target molecules, or both. The compounds of this invention may be used as medicaments.


PubMed | Galantos Pharma
Type: Journal Article | Journal: Journal of receptor and signal transduction research | Year: 2010

Galantamine is an approved drug treatment for Alzheimers disease. Initially identified as a weak cholinesterase inhibitor, we have established that galantamine mainly acts as an allosterically potentiating ligand (APL) of nicotinic acetylcholine receptors (nAChR). Meanwhile other positive allosteric modulators (PAM) of nAChR channel activity have been discovered, and for one of them a binding site within the transmembrane domain has been proposed. Here we show, by performing site-directed mutagenesis studies of ectopically expressed chimeric chicken 7/mouse 5-hydroxytryptamine 3 receptor-channel complex, in combination with whole-cell current measurements, in the presence and absence of galantamine, that the APL binding site is different from the proposed PAM binding site. We demonstrate that residues T197, I196, and F198 of -strand 10 represent major elements of the galantamine binding site. Residue K123, earlier suggested as being close to the APL binding site, is not part of this site but rather appears to play a role in coupling of agonist binding to channel opening and closing. Our data confirm our earlier results that the galantamine binding site is different from the ACh binding site. Both sites are in close proximity and hence may influence each other in a synergistic fashion. Other interesting areas identified in the present study are a hinge region around and containing residues F122, K123, and K143 possibly being involved in relaying the signal of agonist binding to gating of the transmembrane channel, and a folding centre, with P119 as the dominating residue, that crucially positions the agonist binding site with respect to the hinge region.


Trademark
Galantos Pharma | Date: 2011-07-05

pharmaceutical preparations for the treatment of Alzheimer disease, dementia and Parkinsons disease; pharmaceutical preparations and products for treating diseases and disorders of the central nervous system; veterinary preparations for treating diseases and disorders related to the central nervous system, alzheimers disease the treatment of other dementias and parkinsons disease for domesticated animals, rats, mice and livestock; sanitary preparations for medical use; pharmaceutical preparations and products for treating diseases and disorders of the central nervous system, for the treatment of alzheimers disease, for the treatment of other dementia, and for the treatment of parkinsons disease, nootropics; pharmaceutical preparations for the treatment of schizophrenia, antidepressants, geriatric preparations, namely, pharmaceutical preparations and products for treating diseases and disorders of the central nervous system, for the treatment of alzheimers disease, for the treatment of other dementias, and for the treatment of parkinsons disease; pharmaceutical preparations, namely, acetyloholinesterase inhibitors for the treatment of diseases and disorders of the central nervous system, for the treatment of alzheimers disease, for the treatment of other dementias, and for the treatment of parkinsons disease; pharmaceutical preparations, namely, cholinergic enhancers for the treatment of diseases and disorders of the central nervous system, for the treatment of alzheimers disease, for the treatment of other dementias, and for the treatment of parkinsons disease; pharmaceutical preparations, namely, cholinomimetics for the treatment of diseases and disorders of the central nervous system, for the treatment of alzheimers disease, for the treatment of other dementias, and for the treatment of parkinsons disease. Pharmaceutical research and development services.


PubMed | Leibniz Institute for Neurobiology and Galantos Pharma
Type: Journal Article | Journal: Journal of Alzheimer's disease : JAD | Year: 2015

The plant alkaloid galantamine is an established symptomatic drug treatment for Alzheimers disease (AD), providing cognitive and global relief in human patients. However, as an acetylcholinesterase inhibitor, gastrointestinal side effects limit the dosage and duration of treatment. Memogain (Gln-1062), a pro-drug, liberates galantamine on cleavage by a carboxyesterase in the brain. The possibility to deliver Memogain intranasally may further circumvent side effects, allowing higher dosing compared to galantamine. In this study, the 5X Familial Alzheimers Disease (5XFAD) mouse model was used to investigate the effect of chronic Memogain treatment on behavior and amyloid- (A) plaque deposition in the brain. Chronic intranasal dosage of 6mg/kg body weight twice daily was tolerated well, whereas the double dose caused body weight loss in males and was less effective in some behavioral tests. 8 weeks of chronic treatment resulted in improved performance in behavioral tests, such as open field and light-dark avoidance, and in fear conditioning already at mildly affected stages at the age of 18 weeks compared to untreated controls. Furthermore, after treatment a significantly lower plaque density in the brain, i.e., in the entorhinal cortex (reduction 20% females, 40% males) and the hippocampus (19% females, 31% males) at the age of 18 weeks was observed. These results show that nasal application of Memogain effectively delivers the drug to the brain with the potential to retard plaque deposition and improve behavioral symptoms in AD similar to the approved galantamine.

Loading Galantos Pharma collaborators
Loading Galantos Pharma collaborators