3-Nitropropionic acid as a tool to study the mechanisms involved in Huntington's disease: past, present and future

Abstract

Huntington's disease (HD) is an inheritable autosomal-dominant disorder whose causal mechanisms remain unknown. Experimental models have begun to uncover these pathways, thus helping to understand the mechanisms implicated and allowing for the characterization of potential targets for new therapeutic strategies. 3-Nitropropionic acid is known to produce in animals behavioural, biochemical and morphologic changes similar to those occurring in HD. For this reason, this phenotypic model is gaining attention as a valuable tool to mimick this disorder and further developing new therapies. In this review, we will focus on the past and present research of this molecule, to finally bring a perspective on what will be next in this promising field of study.

Figure 1

3-NP irreversibly inhibits succinate dehydrogenase (SDH; complex II) of electron transport chain (ETC) and tricarboxylic acid cycle. Schematic representation of the effect of 3-NP on ETC. IM: inner membrane; IMS: Intermembrane space; OM: outer membrane. Complex I: NADH dehydrogenase; Complex III: Cytochrome bc₁ or cytochrome c reductase; Complex IV: Cytochrome c oxidase; Complex V: ATP synthase.

Figure 2

Neurotoxicity by 3-NP: 3-NP promptes complex II inhibition and increased sensibility of NMDA-R (excitotoxicity). 3-NP toxicity affects microglia, astrocytes and neurons, and causes secondary excitotoxicity by making neurons more vulnerable to endogenous basal levels of glutamate, while prompting a reduction of ATP availability. This scenario causes relief of voltage-dependent Mg²⁺ blockade at the NMDA-R pore. In turn, the activation of these receptors leads to massive entry of Ca²⁺ to cytoplasm and further activation of a number of calcium dependent enzymes, including calpains and NOS. Alltogether, these events lead to cell death by different pathways: necrosis and/or apoptosis, depending of intensity of insult and cell type. ETC: Electron transport chain; LDH: Lactate dehydrogenase; mΔψ: Membrane potential; NMDA-R: N-methyl D-aspartate (NMDA) receptor; 3-NP: 3-Nitropropionic acid; RNS: Reactive nitrogen species; ROS: Reactive oxygen species.

Figure 3

Activation of protective genes by 3-NP. 3-NP triggeres the transcriptional activation of vitagenes expression, which encoded phase II detoxification enzymes, by mean of antioxidant response element (ARE). COX-2: Cyclooxygenase 2; GST: Glutathione S transferase; HO-1: Hemeoxygenase 1; NADPH: Nicotinamide adenine dinucleotide phosphate; 3-NP: 3-Nitropropionic acid; NQ01: NADPH quinine oxidoreductase 1; Nrf2: Nuclear Factor-E2-related factor 2; NFκβ: Nuclear factor kappa beta; ROS. Reactive oxygen species; RNS: Reactive nitrogen species; TRXr: Thioredoxin reductase; UGT: Uridine 5’-diphosphate glucuronosyltransferase. Ikb: Inhibitor of NFκβ; Keap1: Inhibitor of Nrf2; Small Maf: Transcriptional repressors or transcriptional coactivators.