Neuro-inflammation, neurotrophic factors and neuroprotection

The role of astrocyte-neuronal interactions in multiple sclerosis

PIs: Jacques De Keyser, Ron Kooijman, Ann Massie
PhD students: Frauke Demol, Guy Laureys
Post-doc: Cathy Jensen

Astrocytes are the main cellular targets of noradrenergic terminals in the brain. Stimulation of astrocytic glycogenolysis is mediated by noradrenaline acting on ß2 adrenergic receptors (ß2AR), a process that appears to be modulated by a variety of neuropeptides (e.g. VIP). Increases in ß2AR-mediated cAMP are involved in the synthesis of a variety of trophic factors, suppression of immune-inflammatory responses through inhibition of the transcription factor NF-kB, and inhibition of astrocyte proliferation (astrogliosis), pointing out that the astrocyte ß2AR-cAMP pathway might serve as novel target for neuroprotective therapies. A dysfunction of this pathway is suspected to play an important role in the pathophysiology of MS, since our group has discovered that astrocytes in MS are deficient in ß2Ars.

The major research questions are: how can we obtain neuroprotective effects by modulating the astrocytic noradrenergic/cAMP system, and what is the role and cause of the loss of astrocytic ß2ARs in MS?

  • What is the neurobiochemical, behavioral and pathological phenotype of our recently developed astrocyte-selective ß2AR KO mouse (astroß2AR KO)? Could this represent a new animal model for MS? Can the deficit and disease manifestations be restored by ß2AR gene therapy?
  • What is the role of the astrocytic ß2AR-cAMP signaling pathway in astrocyte metabolism, cerebral perfusion, and immune modulation in vivo in animal models and in patients?
  • What other transmitter systems activate or influence the astrocytic cAMP-signaling pathway, for example to compensate for the loss of the astrocytic ß2AR observed in MS? Is the PKA or EPAC signaling pathway involved?
  • Is a viral infection of astrocytes responsible for the loss of astrocytic ß2ARs in MS, and what is the underlying mechanism? 
  • Can we improve the disease course of MS by activating or modulating the ß2AR/cAMP-signaling pathway (in MS through the cAMP signaling pathway) and can we identify neuroprotective compounds that can be used in the clinic?

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

PIs: Ron Kooijman, Jacques De Keyser
PhD students: Wendy Stoop, Ann De Smedt

Stroke is the most common cause of adult disability and ischemic stroke represents about 85% of all cases. Until now, the only approved acute treatment of ischemic stroke is reperfusion by tissue-plasminogen activator, but only 10-15% of the patients benefit from this treatment. On the other hand, we have provided proof-of-principle for neuroprotection by post-stroke systemic administration of recombinant human (rh)IGF-I or estradiol in a rat model of ischemic stroke. Furthermore, we showed that systemically administered rhIGF-I passes the blood brain barrier in normal rats leading to physiologically relevant concentrations of rhIGF-I in the brain (1.2 ng/mg protein and 0.6-4.5 ng/ml in the extracellular space as assessed by microdialysis). Using an IGF-I receptor antagonist, we also provided evidence that intravenously injected rhIGF-I acts directly through interaction with its receptors in the brain. Furthermore, both rhIGF-I and estradiol affect the activation/differentiation of microglia after stroke.

The major research questions are: What are the basic mechanisms of neuroprotection by IGF-I and estradiol in ischemic stroke and how can we optimize the treatment protocol for neuroprotection?

  • Which events of the ischemic cascade (excitotoxicity, neuroinflammation, oxidative stress, different forms of neuronal cell death) are modulated by systemic administration of IGF-I?
  • What is the role of microglia in neuroprotection?
  • Insight into the working mechanism will support the development of combination therapies with drugs exerting complementary actions on the ischemic cascade.
  • Do IGF-I and estradiol act in synergy in the ischemic brain as observed in models for epilepsy and Parkinson’s disease?
  • Can we stimulate IGF-I transport to the brain or the local expression of endogenous IGF-I in astrocytes?
  • Does long term expression of IGF-I in the brain through injection of adeno-associated virus-based vectors lead to neuroprotection or recovery?

Neuroprotection by hypothermia in ischemic stroke

PIs: Ron Kooijman, Said Hachimi-Idrissi, Ilse Smolders, Jacques De Keyser
Post-doc: Joline Goossens

We have shown that a short post-stroke treatment protocol for hypothermia inhibits apoptosis and decreases infarct size which correlates well with a decreased sensorimotor impairment. These effects are maintained for up to one week and go along with a decrease in neuroinflammation at three days after the insult and an increase in neuroinflammation at one week after stroke. Furthermore, by differential display we have identified proteins of which the expression levels are corrected by hypothermia.

We will focus on the working mechanism of neuroprotection and the development of biomarkers

  • Are the effects of hypothermia on neuroinflammation beneficial or detrimental?
  • Are proteins of which the expression levels are restored by hypothermia involved in neuroprotection?
  • Is it possible to obtain neuroprotection by a more specific and direct regulation of these proteins?
  • Can we develop biomarkers predicting the efficacy of hypothermia for different patients?


Centre for Neurosciences • Vrije Universiteit Brussels • ©2017 • •
Faculty of Medicine & Pharmacie • Laarbeeklaan 103 • 1090 Brussel, BELGIUM • Tel: +32 (2) 477 64 10
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