Comparative toxicities of amphotericin B and its monomethyl ester derivative on glial cells in culture
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Published on: May 5, 2009
S P Racis1, O J Plescia, H M Geller
1Waksman Institute of Microbiology, Rutgers, State University of New Jersey, New Brunswick 08903.
Abstract:
Amphotericin B (AmB) is a potent antifungal polyene macrolide antibiotic and is the drug of choice for the treatment of deep-seated mycotic infections. Its use is limited, owing to its nephrotoxicity, and it must be dispersed in deoxycholate for parenteral administration. In contrast, AME (the monomethyl derivative of AmB) is water dispersible, is appreciably less cytotoxic than AmB toward a variety of cell types, and is reportedly active against the acquired immunodeficiency syndrome virus (human immunodeficiency virus type 1). The latter activity has generated interest in AME as an antiviral drug. However, AME is perceived to be neurotoxic, based on the outcome of a human clinical trial of AME as an antifungal drug. AmB is not regarded as neurotoxic, presumably because any neurotoxicity in vivo is precluded by its nephrotoxicity. It was important, therefore, to determine the potential for neurotoxicity of the two agents in comparative tests, assessing the effects of their direct action against neural cells in culture. Rat cortical cells, comprising astrocytes and oligodendrocytes, were used. AME was at least 10 times less toxic than AmB and equally less toxic against several other nonneural cell types also included in these tests. Equally important, AmB disrupted the myelin sheath in these cultures, and it inhibited its generation. AME did not, even at a concentration 10 times greater than the toxic concentration of AmB. AmB is, therefore, potentially more neurotoxic than AME, contrary to current perception. AME is effective as an antifungal and antiviral drug at a concentration far below its toxic concentration for neural cells. Also, AME does not cross the blood-brain barrier appreciably, so that a therapeutic level in blood can be expected without encountering neurotoxicity.
Insights
Amphotericin B (AmB) and its derivative AME were compared for neurotoxicity. AME showed significantly lower toxicity to neural cells and did not disrupt myelin, challenging the perception of AME as neurotoxic.
Area of Science:
- Neuroscience
- Pharmacology
- Mycology
Background:
- Amphotericin B (AmB) is a critical antifungal but limited by nephrotoxicity.
- Its derivative, AME, is water-dispersible, less cytotoxic, and shows antiviral activity.
- AME is perceived as neurotoxic, while AmB is not, likely due to AmB's nephrotoxicity masking neurotoxic effects.
Purpose of the Study:
- To directly compare the neurotoxicity of AmB and AME on neural cells in culture.
- To investigate the effects of AmB and AME on myelin sheath integrity and generation.
Main Methods:
- Primary rat cortical cells, including astrocytes and oligodendrocytes, were cultured.
- Comparative toxicity assays were performed for AmB and AME.
- Effects on myelin sheath disruption and generation were assessed.
Main Results:
- AME was at least 10 times less toxic than AmB to neural cells.
- AmB disrupted and inhibited myelin sheath generation in vitro.
- AME did not exhibit these neurotoxic effects, even at higher concentrations than toxic levels of AmB.
Conclusions:
- Contrary to perception, AmB may be more neurotoxic than AME.
- AME demonstrates a favorable safety profile for neural cells at therapeutic concentrations.
- AME's limited blood-brain barrier penetration suggests a lower risk of central nervous system toxicity.
