The 2-deoxyglucose uptake method as a first screen for neurotoxic compounds

Our primary goal is to develop a screening procedure to detect and partially characterize neurotoxic compounds. There is a great need for a new approach to screening for neurotoxicants because our industrialized world abounds with untested and potentially neurotoxic compounds. A large number of new compounds are introduced each year. Although a number of testing approaches to the screening for neurotoxicants have been proposed in the recent years, a consensus on the most adequate approach is yet to emerge. The existing methods share a number of shortcomings. Thus, most methods only detect a fraction of the tested neurotoxicants. Other methods lack the necessary resolution to detect the neurotoxic damage reproducibly and reliably. Furthermore, many screening approaches are too time consuming and costly to be used for the large-scale screening of neurotoxicants. It is, therefore, imperative to develop reliable and efficient screening methods applicable in regulatory toxicology. In this report, we describe two versions of the same method that we feel may be very beneficial for the large-scale screening of neurotoxicants. The 2-deoxyglucose (2-DG) uptake method provides an indirect measure of neuronal activity in different areas of the brain. The ability of the method to detect most, if not all, neuroactive substances is reviewed in this report. In the context of this report, a neuroactive substance is defined as a substance acting directly on the central or peripheral nervous system neurons and (or) glia. The 2-DG method equals the sensitivity of the most sensitive alternative methods which were selectively designed to detect the effects of specific groups of compounds. The generality and sensitivity of the 2-DG method are of major importance. Thus, if a tested compound does not affect the uptake of 2-DG into the brain, it is not likely to be neuroactive. Since neurotoxic compounds are a subset of neuroactive compounds, a compound that is not neuroactive is also not neurotoxic. Thus, a single test may, in some instances, determine if a tested compound is nontoxic. In addition, it appears that each compound or, at least, each family of compounds produces a characteristic profile ("pattern") of the sites of altered 2-DG uptake. This pattern can be exploited to characterize the tested compound and help us decide whether it is neurotoxic or neuroactive. Preliminary results from our laboratory indicate classical neurotoxic agents such as acrylamide, triethyltin, and 2,5-hexanedione induce a generalized depression of the 2-DG uptake throughout the brain. As a result, it may be difficult to differentiate these compounds on the basis of their respective 2-DG pattern. On the other hand, most of the therapeutics tested to date have distinct 2-DG uptake patterns which may help to distinguish therapeutics from classicial neurotoxicants. Additional experimental work is required to clarify this matter. The method has not been extensively used in the field of toxicology, mainly because the existing original 2-DG method is too complex and expensive for the large-scale screening for neurotoxicants. In this report, we review the efforts made to simplify this method as a general neurotoxicology screen. Our initial experience with this method in testing for neurotoxic compounds is also reviewed.