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NEURO-INFLAMMATION, NEUROTROPHIC FACTORS AND NEUROPROTECTION

Neuroprotection by administration of neurotrophic factors in animal models for ischemic stroke

Stroke is the most common cause of adult disability and ischemic stroke represents about 85% of all cases. Until now, only 10-15% of the patients benefit from the only approved treatment for ischemic stroke. We have provided proof-of-principle for neuroprotection by post-stroke systemic administration of recombinant human (rh)IGF-I in a rat model of ischemic stroke. We showed that systemically injected IGF-I passes the blood-brain barrier and exerts anti-inflammatory actions at the level of the microglia. In addition, it appeared that neuroprotection by estradiol is also mediated by IGF-receptors in the brain. Neuroinflammation is a common process in many neurological disorders and neuroinflammation as a target for therapeutics is being investigated in collaboration with other projects at the C4N, e.g. the use of Ghrelin receptor antagonists in epilepsy. Here, we focus on the interaction between neuroinflammation and survival and cell death in neurons in response to Ghrelin receptor stimulation.

The role of astrocyte-neuronal interactions in multiple sclerosis

We will be building further on the finding that in post-mortem Multiple Sclerosis lesions excessive amounts of the vasoconstrictor peptide endothelin-1 (ET-1) are produced by reactive astrocytes, which gives rise to cerebral hypoperfusion, enhanced blood-brain-barrier permeability, inflammatory reactions, excitotoxicity and astrogliosis. Counteracting these harmful effects of astrocytic ET-1 may represent a promising therapeutic approach for MS. We discovered that increased ET-1 expression in astrocytes is triggered by inflammatory cytokines and that this process can be blocked by inhibition of the cholesterol synthesis pathway by statins.

PI

Ron Kooijman

C4N researchers

Ahmad SerhanĀ 

Stephanie Hostenbach