Combination therapy of glucocorticoids and proteasome inhibitors

Many disorders of the CNS change the functionality and integrity of the BBB. Glucocorticoids (GC) are being used successfully in the treatment of some disorders while their effects on others are questionable and the nature of the underlying molecular mechanisms is still a matter of debate. While glucocorticoids potently stabilize the blood brain barrier in neoplastic and inflammatory central nervous system disorders, they are however ineffective in other diseases of the CNS affecting BBB integrity.

Excessive proteasomal glucocorticoid receptor degradation has been identified as an important mechanism causing pharmacological insensitivity of brain microvascular endothelial cells to glucocorticoids in ischemic brain disorders like acute ischemic stroke. In vitro and in vivo, restoration of glucocorticoid sensitivity and effective edema reduction was achieved by inhibition of the proteasomal pathway by Bortezomib accompanied by treatment with a specific glucocorticoid.

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