Michael A. Collins, Ph.D.
Division of Biochemistry
Ph.D. Purdue University
Post-Doctoral Fellowship, Columbia University
Interest: Alcohol as neurotoxicant and neuroprotectant
This laboratory is interested in mechanisms of brain neurodegeneration as well as neuroprotection relevant to alcohol (ethanol). Our past studies with adult rats in collaboration with Dr. E.J. Neafsey clarified that subchronic, repetitive alcohol intoxication sufficient to achieve the high blood levels reported in “binging” alcoholics causes brain edema as well as neurodegeneration largely in the hippocampus and temporal cortex. The facts that diuretics that prevent brain edema neuroprotect, whereas antagonists to glutamate receptors, calcium channels, and nitric oxide synthase do not, suggest a key role for nonsynaptic brain overhydration as opposed to synaptic excitotoxicity. Organotypic rat hippocampal-entorhinal cortical slice cultures are employed by us to further study binge alcohol’s mechanisms in vitro. With these cultures, diuretics, phospholipase A2 inhibitors, antioxidants, and an inhibitor of astroglial-rich aquaporin-4 water channels are neuroprotective against binge alcohol, indicating that aquaporin-4 activity underlies the brain edema, which then triggers damaging oxidative stress in part by mobilizing omega-6 arachidonic acid (AA). We also found neuroprotection by an omega-3 (fish oil) fatty acid, which prevents the elevated AA mobilization. On the other hand, preconditioning brain slice cultures over several days with low-moderate alcohol concentrations promotes a “neuroprotected” state—specifically against HIV-1 gp120 or amyloid-beta, two potent neuroinflammatory proteins linked to dementia in AIDS and Alzheimer’s. Examining temporal events induced by such moderate alcohol preconditioning, we find that NMDA glutamatergic receptors are possible early sensors. Later upregulation of protein kinases such as PKC and focal adhesion kinase suggests that they function as transducers, with their inhibition abolishing subsequent increases in neuroprotective heat shock proteins (hsp70; hsp27) that may be among the ultimate effectors. We speculate that this mechanism could in part underlie reported neuropreventative actions of moderate alcohol intake against dementia in older individuals.
View a partial list of Dr. Collins' publications through the National Library of Medicine's PubMed online database.