Stroke, Neurodegeneration and Diabetes

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Research group Cesare Patrone

The focus is along two major research lines:

  1. The identification of efficacious preclinical therapies for the treatment of stroke.
  2. The study of the cellular mechanisms at the basis of the neurological complications of diabetes.

Stroke affects several million people worldwide, of which a substantial proportion of cases present in patients suffering from diabetes. Diabetes is widespread and represents the fourth leading cause of death in the U.S. About 90 % of the medical and social costs associated with diabetes are dominated by care for macrovascular complications such as stroke.

Alzheimer's disease, dementia and cognitive dysfunction are also overrepresented in diabetes. However, the underlying mechanisms at the basis of this are still largely unknown.

Recent data published by our research group (see below refs 1-5) indicate that the activation of  the glucagone-like receptor 1 (GLP-1R) is neuroprotective against stroke in normal and type 2 diabetic rodents.

We have also shown that a rat model of type 2 diabetes presents neuronal loss and neuroinflammation along aging (ref. 6) These results have the potential to help understanding how and when diabetes leads to neurodegeneration.

We also showed that diabetic glucolipotoxicity negatively impacts adult neural stem cells and that neuropeptides Galanin and PACAP can counteract diabetes-induced cell death (refs 7-8).

Research Group

Cesare Patrone, Research group leader

Vladimer Darsalia, Assistant professor

Grazyna Lietzau, Post doc

Martin Larsson, PhD student (30%)

Preclinical , at KI SÖS we actively cooperate with the research group Diabetes led by Associate professor Thomas Nyström.

Our research is translational, and we also cooperate with Dr David Nathanson, Internal Medicine at Södersjukhuset, who is main supervisor of Dr Martin Larsson (PhD student) for the clinical ramifications of our projects.

Externally, we have ongoing partnerships with the Professors Claes-Göran Östensson and Tomas Hökfelt (KI), with Dr. Ida Nilsson (KI) , with Professor Carina Mallard and Dr. Maria E Johansson (University of Gothenburg) , with Professor Dan Lindholm (University of Helsinki) and with Dr. Simone Beretta (University of Milan) . We also have an ongoing collaboration with Boehringer Ingelheim Pharma GmbH & Co. KG , Germany.

Selected Publications

1. 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 Obes Metab 2016 May;18(5):537-41

2. 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 C, Darsalia V, Patrone C
Oncotarget 2016 Feb;7(5):5865-76

3. 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
J. Cereb. Blood Flow Metab. 2015 May;35(5):718-23

4. 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

5. 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 Apr;62(4):1289-96

6. Diabetes drugs and neurological disorders: new views and therapeutic possibilities.
Patrone C, Eriksson O, Lindholm D
Lancet Diabetes Endocrinol 2014 Mar;2(3):256-62

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

8. Evidence for cortical neuronal loss in male type 2 diabetic Goto-Kakizaki rats.
Hussain S, Mansouri S, Sjöholm , Patrone C, Darsalia V
J. Alzheimers Dis. 2014 ;41(2):551-60

9. Pituitary adenylate cyclase-activating polypeptide counteracts the impaired adult neural stem cell viability induced by palmitate.
Mansouri S, Ortsäter H, Pintor Gallego O, Darsalia V, Sjöholm A, Patrone C
J. Neurosci. Res. 2012 Apr;90(4):759-68

10. 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
J. Neurochem. 2013 Oct;127(2):209-20