The peripheral-type
benzodiazepine receptor is a
mitochondrial protein expressed at high levels in
steroid synthesizing tissues, including the glial cells of the brain. Peripheral-type
benzodiazepine receptor binds
cholesterol with high affinity and is a key
element of the
cholesterol mitochondrial import machinery responsible for supplying the substrate
cholesterol to the first steroidogenic
enzyme, thus initiating and maintaining
neurosteroid biosynthesis.
Neurosteroid formation and metabolism of
steroid intermediates are critical components of normal brain function. Peripheral-type
benzodiazepine receptor also binds with high affinity various classes of compounds. Upon
ligand activation peripheral-type
benzodiazepine receptor-dependent
cholesterol transport into mitochondria is accelerated leading in increased formation of
neuroactive steroids. These
steroids, such as
allopregnanolone, have been shown to be involved in various
neurological disorders, such as anxiety and
mood disorders. Thus, peripheral-type
benzodiazepine receptor drug ligand-induced
neuroactive steroid formation offers a means to regulate brain dysfunction. Peripheral-type
benzodiazepine receptor basal expression is upregulated in a number of neuropathologies, including
gliomas and
neurodegenerative disorders, as well as in various forms of
brain injury and
inflammation. In
Alzheimer's disease pathology
neurosteroid biosynthesis is altered and a decrease in the intermediate
22R-hydroxycholesterol levels is observed. This
steroid was found to exert neuroprotective properties against
beta-amyloid neurotoxicity. Based on this observation, a stable spirostenol derivative showing to display neuroprotective properties was identified, suggesting that compounds developed based on critical intermediates of
neurosteroid biosynthesis could offer novel means for neuroprotection. In conclusion, changes in peripheral-type
benzodiazepine receptor and
neurosteroid levels are part of the phenotype seen in neuropathology and
neurological disorders and offer potential targets for new
therapies.