Homocysteine aggravates ROS-induced depression of transmitter release from motor nerve terminals: potential mechanism of peripheral impairment in motor neuron diseases associated with hyperhomocysteinemia

Abstract

Homocysteine (HCY) is a pro-inflammatory sulphur-containing redox active endogenous amino acid, which concentration increases in neurodegenerative disorders including amyotrophic lateral sclerosis (ALS). A widely held view suggests that HCY could contribute to neurodegeneration via promotion of oxidative stress. However, the action of HCY on motor nerve terminals has not been investigated so far. We previously reported that oxidative stress inhibited synaptic transmission at the neuromuscular junction, targeting primarily the motor nerve terminals. In the current study, we investigated the effect of HCY on oxidative stress-induced impairment of transmitter release at the mouse diaphragm muscle. The mild oxidant H2O2 decreased the intensity of spontaneous quantum release from nerve terminals (measured as the frequency of miniature endplate potentials, MEPPs) without changes in the amplitude of MEPPs, indicating a presynaptic effect. Pre-treatment with HCY for 2 h only slightly affected both amplitude and frequency of MEPPs but increased the inhibitory potency of H2O2 almost two fold. As HCY can activate certain subtypes of glutamate N-methyl D-aspartate (NMDA) receptors we tested the role of NMDA receptors in the sensitizing action of HCY. Remarkably, the selective blocker of NMDA receptors, AP-5 completely removed the sensitizing effect of HCY on the H2O2-induced presynaptic depressant effect. Thus, at the mammalian neuromuscular junction HCY largely increases the inhibitory effect of oxidative stress on transmitter release, via NMDA receptors activation. This combined effect of HCY and local oxidative stress can specifically contribute to the damage of presynaptic terminals in neurodegenerative motoneuron diseases, including ALS.

Homocysteine augments BK channel activity and decreases exocytosis of secretory granules in rat GH3 cells

“…Furthermore, Hcy decreased basal and evoked exocytosis of secretory granules and these effects were partially prevented by the inhibition of BK channels by paxilline and were reversed by the ROS scavenger-N-acetylcysteine. Generation of ROS is one of the known mechanisms of Hcy action [5,6,29]. Our data are likely to provide new insights into the understanding of impairments during the diseased HHcy state.…”

“…Hcy may undergo remethylation to methionine by methylenetetrahydrofolate reductase (MTHFR) with vitamin B12 as a cofactor and folate as a promotor. HHcy is a well-known risk factor for cardio-vascular diseases, neurodegenerative disorders, common pregnancy complications, [3,4] and induces proinflammatory and pro-oxidative conditions [2,[4][5][6]. Genetic mutations of the enzymes MTHFR and CBS as well as nutritional deficiencies of vitamin cofactors (folate, B12, and B6) are the primary causes of hyper-homocysteinemia (HHcy)-a disease due to elevated Hcy plasma levels [2].…”

Hen egg carotenoids (lutein and zeaxanthin) and nutritional impacts on human health: a review

“…These properties of lutein may possibly cause decline in mitochondrial dysfunction and apoptotic death, indicating importance of lutein in treating Alzheimer's. Homocysteine (Hcy), a sulfur containing nonprotein amino acid naturally present in the plasma, is implicated as a risk factor for numerous diseases owing largely to its free radical generating potency (Bonetti, Brombo, & Zuliani, 2016;Bukharaeva, Shakirzyanova, Khuzakhmetova, Sitdikova, & Giniatullin, 2015;Kamat, Vacek, Kalani, & Tyagi, 2015;Paul & Borah, 2015;Sharma, Kumar, Dar, & Singh, 2015). Also, epidemiological studies have found associations between high serum level of Hcy and Alzheimer's disease (AD) progression that eventually leads to vascular dementia (VaD).…”

Prenatal hyperhomocysteinemia induces oxidative stress and accelerates ‘aging’ of mammalian neuromuscular synapses

“…In a previous study we have shown that HCY amplified the inhibitory effects of H 2 O 2 on spontaneous acetylcholine release in mouse neuromuscular junction through activation of NMDA receptors (Bukharaeva et al, 2015). Recently, these findings were supported by Wang et al (2018), where the involvement of nitric oxide in the sensitizing effect of HCY to ROS was revealed.…”

“…Oxidative stress is one of the mechanisms of the damaging action of HCY known as a powerful oxidant, producing reactive oxygen species (ROS) such as superoxide anion (O 2 − ) and hydrogen peroxide (H 2 O 2 ) (Petras et al, 2014), which affect synaptic transmission at central and peripheral nervous systems (Giniatullin et al, 2006). Recently it was shown that HCY sensitizes neuromuscular junction to the inhibitory effect of H 2 O 2 via activation of NMDA receptors and nitric oxide (Bukharaeva et al, 2015; Wang et al, 2018).…”