As described in this review, the biological role(s) of diet-derived LA are quite diverse (). In fact, to our knowledge there are few compounds as multifaceted as LA as a bioactive agent. It is an inducer of cellular signaling pathways, an insulin mimetic, a hypotriglyceridemic agent, a vasorelaxant/anti-hypertensive compound, a metal chelator, and an adjuvant for neuro-cognitive function. Thus, it will be important to define the precise cause-and-effect relationship between LA and its cellular targets of immediate action. An area that warrants further study is whether LA directly regulates hormonal signals, which in turn initiate downstream biochemical actions on target organs. In this regard, LA stimulates an AMPK-dependent anorectic effect in rodents [107
] and improves learning and short-term memory in aged rodents [4
]. Thus diet-derived LA may owe some of its diverse physiological actions on stimulating neuro-hormonal function and thereby indirectly influencing multiple cell signaling pathways in peripheral tissues.
Proposed biological actions of lipoic acid
In concert with its potential for centralized action, it is also apparent that orally supplied LA affects multiple signaling and transcriptional paradigms at the cellular level. Again, the question that immediately arises is whether LA has multiple or only a few actual cellular targets, in the latter case mediating its strong antioxidant and metabolic effects indirectly. For example, LA acts as an insulin mimetic in that it improves glucose handling; however, the timing to which LA stimulates glucose metabolism is significantly delayed from that of insulin itself. Thus, it is still to be determined whether LA truly targets the insulin-signaling pathway via thiol/disulfide interactions on the insulin receptor or its direct protein substrates or alternatively, indirectly influences this pathway by affecting phosphatases.
As this review was being compiled, we were struck by the lack of consistency and sheer magnitude of dose used to examine LA action, particularly for in vitro models. Low micromolar to millimolar concentrations of LA have been employed for cultured cells where LA has variously been shown to induce apoptosis, directly act as an antioxidant, induce H2O2 release, and stimulate stress response mechanisms to name a few. Considering the transient cellular accumulation of LA following an oral dose, which does not exceed low micromolar levels, it is entirely possible that some of the cellular effects of LA when given at supraphysiological concentrations may be not be clinically or physiologically relevant. This may be particularly important in characterizing the cellular role of LA or DHLA as effective direct-acting cellular antioxidants. One must ask how a dithiol agent that only transiently accumulates at very low levels in vivo could act as a potent antioxidant on a stoichiometric basis. Significantly more research is necessary to understand physiological uptake, accumulation and metabolism of LA and its metabolites in order to set up appropriate cell-based models to examine LA action. Only then will the most biologically relevant cellular actions of LA be elucidated.
Although some important aspects of LA’s mechanism of action in vivo are yet to be uncovered, it is apparent that oral LA supplements are clinically effective in mitigating complications of diabetes and potentially, other vascular diseases. Because current evidence is based mainly on data from rodent studies, additional placebo-controlled trials are advisable to determine the potential for LA to maintain or improve neurological disorders (e.g. Alzheimer’s disease, multiple sclerosis), limit progression of cardiovascular disease, mitigate chronic inflammatory conditions, as well as improve or maintain antioxidant/detoxification defenses that otherwise decline with age. Prior to any large-scale clinical work using LA, an initial focus should be placed on optimizing conditions as to effective dose, as well as identification of the appropriate enantiomeric isoform.