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Stroke, neurodegeneration och diabetes

Vår forskargrupp har två fokusområden: 

  • Identifiering av effektiva behandlingar för stroke vid diabetes genom preklinisk forskning.
  • Undersökning av de cellulära mekanismer som ligger till grund för neurologiska komplikationer vid diabetes.

Stroke drabbar flera miljoner människor varje år i världen, en stor del av dessa personer lider samtidigt av diabetes. Diabetes har blivit epidemisk och är nu den fjärde största dödsorsaken USA. Cirka 90 % av medicinska och omsorgsmässiga kostnader förknippade med diabetes är kopplade till det som kallas makrovaskulära komplikationer, exempelvis stroke. Alzheimers sjukdom, kognitiv svikt och demens är också överrepresenterade vid diabetes. Tyvärr är de underliggande mekanismerna som orsakar detta dåligt utforskade.

Vår grupp har nyligen publicerat data som tyder på att aktivering av receptorn för glukagonlik peptid 1 (GLP-1R) är neuroprotektivt vid stroke, både i diabetiska försöksdjur och vid normal glukosomsättning.

Vi har också visat i en djurmodell att typ 2 diabetes inducerar nervcellsförlust och inflammation i hjärnvävnaden. Dessa resultat kan bidra till att förstå hur och när diabetes leder till demens. Avslutningsvis har våra resultat också visat att glukolipotoxisitet påverkar hjärnans möjlighet till återuppbyggnad negativt och att denna negativa effekt kan motverkas av neuropeptiderna galanin och PACAP.

Publikationer

Gliptin-mediated neuroprotection against stroke requires chronic pretreatment and is independent of glucagon-like peptide-1 receptor (vol 18, pg 537, 2016)
Darsalia V, Larsson M, Lietzau G, Nathanson D, Nystrom T, Klein T, et al
DIABETES OBESITY & METABOLISM 2018;20(4):1086-

Glucagon-like receptor 1 agonists and DPP-4 inhibitors: Anti-diabetic drugs with anti-stroke potential
Darsalia V, Klein T, Nyström T, Patrone C
Neuropharmacology 2018;136(Pt B):280-286

The effect of DPP-4 inhibition to improve functional outcome after stroke is mediated by the SDF-1α/CXCR4 pathway
Chiazza F, Tammen H, Pintana H, Lietzau G, Collino M, Nyström T, et al
Cardiovascular diabetology 2018;17(1):60-

The high need for trials assessing functional outcome after stroke rather than stroke prevention with GLP-1 agonists and DPP-4 inhibitors
Darsalia V, Larsson M, Klein T, Patrone C
Cardiovascular diabetology 2018;17(1):32-

Type 2 diabetes impairs odour detection, olfactory memory and olfactory neuroplasticity; effects partly reversed by the DPP-4 inhibitor Linagliptin
Lietzau G, Davidsson W, Östenson Cg, Chiazza F, Nathanson D, Pintana H, et al
Acta neuropathologica communications 2018;6(1):14-

PACAP Protects Adult Neural Stem Cells from the Neurotoxic Effect of Ketamine Associated with Decreased Apoptosis, ER Stress and mTOR Pathway Activation
Mansouri S, Agartz I, Ögren So, Patrone C, Lundberg M
PloS one 2017;12(1):e0170496-

Type 2 diabetes alters hippocampal gamma oscillations: A potential mechanism behind impaired cognition
Lietzau G, Darsalia V, Pintana H, Östenson Cg, Nyström T, Fisahn A, et al
Psychoneuroendocrinology 2017;82():46-50

Diabetes negatively affects cortical and striatal GABAergic neurons: an effect that is partially counteracted by exendin-4
Larsson M, Lietzau G, Nathanson D, Ostenson Cg, Mallard C, Johansson Me, et al
BIOSCIENCE REPORTS 2016;:-

Gliptin-mediated neuroprotection against stroke requires chronic pretreatment and is independent of glucagon-like peptide-1 receptor
Darsalia V, Larsson M, Lietzau G, Nathanson D, Nyström T, Klein T, et al
Diabetes, obesity & metabolism 2016;18(5):537-41

Pituitary Adenlylate Cyclase Activating Peptide Protects Adult Neural Stem Cells from a Hypoglycaemic milieu
Mansouri S, Lietzau G, Lundberg M, Nathanson D, Nyström T, Patrone C
PloS one 2016;11(6):e0156867-

Type 2 diabetes-induced neuronal pathology in the piriform cortex of the rat is reversed by the GLP-1 receptor agonist exendin-4
Lietzau G, Nyström T, Östenson Cg, Darsalia V, Patrone C
Oncotarget 2016;7(5):5865-76

Glucagon-like receptor 1 agonists and DPP-4 inhibitors: potential therapies for the treatment of stroke
Darsalia V, Larsson M, Nathanson D, Klein T, Nyström T, Patrone C
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 2015;35(5):718-23

Diabetes drugs and neurological disorders: new views and therapeutic possibilities
Patrone C, Eriksson O, Lindholm D
The lancet. Diabetes & endocrinology 2014;2(3):256-62

Evidence for cortical neuronal loss in male type 2 diabetic Goto-Kakizaki rats
Hussain S, Mansouri S, Sjöholm Å, Patrone C, Darsalia V
Journal of Alzheimer's disease : JAD 2014;41(2):551-60

Exendin-4 reduces ischemic brain injury in normal and aged type 2 diabetic mice and promotes microglial M2 polarization
Darsalia V, Hua S, Larsson M, Mallard C, Nathanson D, Nyström T, et al
PloS one 2014;9(8):e103114-

GLP-1R activation for the treatment of stroke: updating and future perspectives
Darsalia V, Nathanson D, Nyström T, Klein T, Sjöholm Å, Patrone C
Reviews in endocrine & metabolic disorders 2014;15(3):233-42

Linagliptin enhances neural stem cell proliferation after stroke in type 2 diabetic mice
Darsalia V, Olverling A, Larsson M, Mansouri S, Nathanson D, Nyström T, et al
Regulatory peptides 2014;190-191():25-31

Sex, diastolic blood pressure, and outcome after thrombolysis for ischemic stroke
Nathanson D, Patrone C, Nyström T, Von Euler M
Stroke research and treatment 2014;2014():747458-

GalR3 activation promotes adult neural stem cell survival in response to a diabetic milieu
Mansouri S, Barde S, Ortsäter H, Eweida M, Darsalia V, Langel U, et al
Journal of neurochemistry 2013;127(2):209-20

Metformin protects against lipoapoptosis and enhances GLP-1 secretion from GLP-1-producing cells
Kappe C, Patrone C, Holst Jj, Zhang Q, Sjöholm A
Journal of gastroenterology 2013;48(3):322-32

The DPP-4 inhibitor linagliptin counteracts stroke in the normal and diabetic mouse brain: a comparison with glimepiride
Darsalia V, Ortsäter H, Olverling A, Darlöf E, Wolbert P, Nyström T, et al
Diabetes 2013;62(4):1289-96

The specific VPAC2 agonist Bay 55-9837 increases neuronal damage and hemorrhagic transformation after stroke in type 2 diabetic rats
Darsalia V, Mansouri S, Wolbert P, Barde S, Sjöholm A, Patrone C
Neuropeptides 2013;47(2):133-7

GLP-1 secretion by microglial cells and decreased CNS expression in obesity
Kappe C, Tracy Lm, Patrone C, Iverfeldt K, Sjöholm Å
Journal of neuroinflammation 2012;9():276-

Glucagon-like peptide-1 receptor activation reduces ischaemic brain damage following stroke in Type 2 diabetic rats
Darsalia V, Mansouri S, Ortsater H, Olverling A, Nozadze N, Kappe C, et al
CLINICAL SCIENCE 2012;122(9-10):473-83

Pituitary Adenylate Cyclase-Activating Polypeptide Counteracts the Impaired Adult Neural Stem Cell Viability Induced by Palmitate
Mansouri S, Ortsater H, Gallego Op, Darsalia V, Sjoholm A, Patrone C
JOURNAL OF NEUROSCIENCE RESEARCH 2012;90(4):759-68

Restorative Effects of Platelet Derived Growth Factor-BB in Rodent Models of Parkinson's Disease
Zachrisson O, Zhao M, Andersson A, Dannaeus K, Haggblad Jh, Isacson R, et al
JOURNAL OF PARKINSONS DISEASE 2011;1(1):49-63

The glucagon-like peptide 1 receptor agonist exendin-4 improves reference memory performance and decreases immobility in the forced swim test
Isacson R, Nielsen E, Dannaeus K, Bertilsson G, Patrone C, Zachrisson O, et al
EUROPEAN JOURNAL OF PHARMACOLOGY 2011;650(1):249-55

Peptide hormone exendin-4 stimulates subventricular zone neurogenesis in the adult rodent brain and induces recovery in an animal model of Parkinson's disease
Bertilsson G, Patrone C, Zachrisson O, Andersson A, Dannaeus K, Heidrich J, et al
JOURNAL OF NEUROSCIENCE RESEARCH 2008;86(2):326-38

Rapid quantification of neurons and stem/progenitor cells in the adult mouse brain by flow cytometry
Hellstom Nak, Zachrisson O, Kuhn Hg, Patrone C
LETTERS IN DRUG DESIGN & DISCOVERY 2007;4(8):532-539

PACAP promotes neural stem cell proliferation in adult mouse brain
Mercer A, Ronnholm H, Holmberg J, Lundh H, Heidrich J, Zachrisson O, et al
JOURNAL OF NEUROSCIENCE RESEARCH 2004;76(2):205-15

Regulation of postnatal lung development and homeostasis by estrogen receptor beta
Patrone C, Cassel Tn, Pettersson K, Piao Ys, Cheng Gj, Ciana P, et al
MOLECULAR AND CELLULAR BIOLOGY 2003;23(23):8542-52

Estradiol induces differential neuronal phenotypes by activating estrogen receptor alpha or beta
Patrone C, Pollio G, Vegeto E, Enmark E, De Curtis I, Gustafsson Ja, et al
ENDOCRINOLOGY 2000;141(5):1839-45

Oestrogen prevention of neural cell death correlates with decreased expression of mRNA for the pro-apoptotic protein Nip-2
Meda C, Vegeto E, Pollio G, Ciana P, Patrone C, Pellicciari C, et al
JOURNAL OF NEUROENDOCRINOLOGY 2000;12(11):1051-9

Estrogen receptor-dependent regulation of sensory neuron survival in developing dorsal root ganglion
Patrone C, Andersson S, Korhonen L, Lindholm D
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 1999;96(19):10905-10

Pituitary adenylate cyclase activating polypepetide is expressed by developing rat Purkinje cells and decreases the number of cerebellar gamma-amino butyric acid positive neurons in culture
Skoglosa Y, Patrone C, Lindholm D
NEUROSCIENCE LETTERS 1999;265(3):207-10

Divergent pathways regulate ligand-independent activation of ER alpha in SK-N-BE neuroblastoma and COS-1 renal carcinoma cells
Patrone C, Gianazza E, Santagati S, Agrati P, Maggi A
MOLECULAR ENDOCRINOLOGY 1998;12(6):835-41

Dopaminergic phenotype induced by oestrogens in a human neuroblastoma cell line
Agrati P, Ma Zq, Patrone C, Picotti Gb, Pellicciari C, Bondiolotti G, et al
EUROPEAN JOURNAL OF NEUROSCIENCE 1997;9(5):1008-16

Dopaminergic phenotype induced by oestrogens in a human neuroblastoma cell line (vol 9, pg 1008, 1997)
Agrati P, Ma Zq, Patrone C, Picotti Gb, Pellicciari C, Bondiolotti G, et al
EUROPEAN JOURNAL OF NEUROSCIENCE 1997;9(7):1552-1552

Oligonucleotide squelching reveals the mechanism of estrogen receptor autologous down-regulation
Santagati S, Gianazza E, Agrati P, Vegeto E, Patrone C, Pollio G, et al
MOLECULAR ENDOCRINOLOGY 1997;11(7):938-49

SK-ER3 neuroblastoma cells as a model for the study of estrogen influence on neural cells
Agrati P, Garnier M, Patrone C, Pollio G, Santagati S, Vegeto E, et al
BRAIN RESEARCH BULLETIN 1997;44(4):519-23

Cross-coupling between insulin and estrogen receptor in human neuroblastoma cells
Patrone C, Ma Zq, Pollio G, Agrati P, Parker Mg, Maggi A
MOLECULAR ENDOCRINOLOGY 1996;10(5):499-507

SPECIFICITY OF ACTION OF A HERPES-VIRUS VP16 TETRACYCLINE-DEPENDENT TRANSACTIVATOR IN MAMMALIAN-CELL CULTURES
Magalini A, Ferrari F, Savoldi G, Ingrassia R, Albertini A, Pollio G, et al
DNA AND CELL BIOLOGY 1995;14(8):665-71

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