Current Challenges with HDAC Inhibitor-Based Therapeutic Intervention Against Neurological Maladies
Histone deacetylase inhibitors (HDACi) have proved their mettle in treating hematological malignancies and are now emerging as propitious agents for tackling neurological complications. However, certain things limit their possible use as therapeutic agents for treating neuronal disorders. Thus this chapter details all the current therapeutic impediments in the pathway of HDACi. Among these roadblocks, lack of sufficient knowledge regarding the individual HDACs in neuronal diseases is one of the concerns, which is discussed. Further, this chapter sheds light on the lack of specificity of HDACi and high structural identity at the active sites of different HDACs. Importantly, the lack of blood-brain barrier permeability of HDACi restricting the use of these marvellous inhibitors against neurological disorders is detailed.
- Ganai SA (2014) In silico approaches towards safe targeting of Class I histone deacetylases. In: Wells RD, Bond JS, Klinman J, Masters BSS, Bell E (eds) Molecular life sciences: an encyclopedic reference. Springer, New York, pp 1–9. https://doi.org/10.1007/978-1-4614-6436-5_459-1 CrossRefGoogle Scholar
- Hanson JE, La H, Plise E, Chen YH, Ding X, Hanania T, Sabath EV, Alexandrov V, Brunner D, Leahy E, Steiner P, Liu L, Scearce-Levie K, Zhou Q (2013) SAHA enhances synaptic function and plasticity in vitro but has limited brain availability in vivo and does not impact cognition. PLoS One 8(7):e69964CrossRefGoogle Scholar
- Kim SW, Hooker JM, Otto N, Win K, Muench L, Shea C, Carter P, King P, Reid AE, Volkow ND, Fowler JS (2013) Whole-body pharmacokinetics of HDAC inhibitor drugs, butyric acid, valproic acid and 4-phenylbutyric acid measured with carbon-11 labeled analogs by PET. Nucl Med Biol 40(7):912–918CrossRefGoogle Scholar
- Rumbaugh G, Sillivan SE, Ozkan ED, Rojas CS, Hubbs CR, Aceti M, Kilgore M, Kudugunti S, Puthanveettil SV, Sweatt JD, Rusche J, Miller CA (2015) Pharmacological selectivity within Class I histone deacetylases predicts effects on synaptic function and memory rescue. Neuropsychopharmacology 40:2307CrossRefGoogle Scholar