Difference between revisions of "Homocysteine"

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''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.'' {{#pmid:26500495|bukharaeva2015}}
 
''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.'' {{#pmid:26500495|bukharaeva2015}}
  
 +
''BBB permeability was measured by Evans blue dye permeation and was found to be 25% greater in the Cbs(+/-) cortex compared with wild-type controls. Our study suggests an important toxic effect of elevated Hcy on brain microvessels and implicates Hcy in the disruption of the BBB.'' {{#pmid:16189268|kamath2006}}
  
 
== References ==
 
== References ==

Revision as of 15:53, 11 August 2017

Key concepts in ALS

Plasma homocysteine (Hcy) levels were significantly increased in patients with amyotrophic lateral sclerosis (ALS) compared with healthy controls. ALS cases with shorter time to diagnosis presented higher Hcy levels, suggesting that higher Hcy may be linked to faster progression of the disease. [1]

Homocysteine (Hcy) exerts multiple neurotoxic mechanisms that have also been shown to be relevant in the pathogenesis of amyotrophic lateral sclerosis (ALS). We reviewed the published evidence to assess possible correlations between Hcy and ALS. A Medline literature search was performed to identify all studies on Hcy and ALS or motor neurons published from 1 January 1966 through 28 February 2009. Twelve studies (one in vitro, eight in vivo, and three studies on human subjects) were reviewed. The in vitro and in vivo animal studies showed that Hcy can damage motor neurons by inducing oxidative stress and stimulating excitotoxic receptors. In preliminary studies on human subjects, ALS subjects had higher median Hcy levels compared to age- and sex-matched controls. Higher Hcy levels were also correlated with a possible marker of disease progression. Finally, a short-term treatment with a high dose of methylcobalamin, which reduces Hcy levels, was effective in improving compound motor action potentials in patients with ALS. In conclusion, several types of evidence show that accumulation of Hcy may increase the risk and progression of motoneuronal degeneration. If this is confirmed, early interventions to decrease Hcy levels may be useful to modify ALS progression and possibly onset. [2]

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. [3]

BBB permeability was measured by Evans blue dye permeation and was found to be 25% greater in the Cbs(+/-) cortex compared with wild-type controls. Our study suggests an important toxic effect of elevated Hcy on brain microvessels and implicates Hcy in the disruption of the BBB. [4]

References

Mendeley group
  1. Zoccolella et al.: Elevated plasma homocysteine levels in patients with amyotrophic lateral sclerosis. Neurology 2008;70:222-5. PMID: 18195267. DOI. BACKGROUND: Both in vitro and in vivo studies indicate that homocysteine (Hcy) may be directly involved in the damage of motor neurons and in several pathways implicated in amyotrophic lateral sclerosis (ALS) pathogenesis. OBJECTIVE: To determine whether plasma Hcy levels were higher in ALS patients than healthy controls and to examine the relationship between Hcy levels and clinical ALS phenotypes. METHODS: In a cross-sectional study, we compared Hcy, B(12), and folate levels in 62 patients with ALS and 88 age- and sex-matched controls recruited as outpatients in a tertiary clinical center. RESULTS: Patients with ALS had higher median plasma Hcy levels (11.2 [range 5.8 to 46] vs 9.7 [range 4.5 to 15.9] micromol/L; p = 0.0004) and lower folate levels (4.4 [range 1.7 to 22.1] vs 5.8 [range 2.3 to 21.1] ng/mL; p = 0.0003), compared with controls. Multivariate logistic regression revealed a strong direct association between plasma Hcy levels and presence of ALS (odds ratios adjusted for age, sex, and B-vitamin levels comparing the top tertile [Hcy levels >or= 11.6 micromol/L] with the bottom tertile [Hcy levels < 9.2 micromol/L]: 6.4; 95% CI 2.2 to 19.1; p for trend = 0.0008). We also found a trend for higher Hcy levels in patients with shorter interval from symptom onset to diagnosis (ODI; <14 months), compared with patients with longer ODI (>14 months; median Hcy levels 11.8 [range 5.8 to 46] vs 10.1 [range 7.2 to 17.6] micromol/L; p = 0.09). In a multivariate model, Hcy levels strongly correlated with shorter interval onset diagnosis (r(2) = 0.18; p = 0.01). CONCLUSIONS: Plasma homocysteine (Hcy) levels were significantly increased in patients with amyotrophic lateral sclerosis (ALS) compared with healthy controls. ALS cases with shorter time to diagnosis presented higher Hcy levels, suggesting that higher Hcy may be linked to faster progression of the disease.
  2. Zoccolella et al.: Homocysteine levels and amyotrophic lateral sclerosis: A possible link. Amyotroph Lateral Scler 2010;11:140-7. PMID: 19551535. DOI. Homocysteine (Hcy) exerts multiple neurotoxic mechanisms that have also been shown to be relevant in the pathogenesis of amyotrophic lateral sclerosis (ALS). We reviewed the published evidence to assess possible correlations between Hcy and ALS. A Medline literature search was performed to identify all studies on Hcy and ALS or motor neurons published from 1 January 1966 through 28 February 2009. Twelve studies (one in vitro, eight in vivo, and three studies on human subjects) were reviewed. The in vitro and in vivo animal studies showed that Hcy can damage motor neurons by inducing oxidative stress and stimulating excitotoxic receptors. In preliminary studies on human subjects, ALS subjects had higher median Hcy levels compared to age- and sex-matched controls. Higher Hcy levels were also correlated with a possible marker of disease progression. Finally, a short-term treatment with a high dose of methylcobalamin, which reduces Hcy levels, was effective in improving compound motor action potentials in patients with ALS. In conclusion, several types of evidence show that accumulation of Hcy may increase the risk and progression of motoneuronal degeneration. If this is confirmed, early interventions to decrease Hcy levels may be useful to modify ALS progression and possibly onset.
  3. Bukharaeva et al.: Homocysteine aggravates ROS-induced depression of transmitter release from motor nerve terminals: potential mechanism of peripheral impairment in motor neuron diseases associated with hyperhomocysteinemia. Front Cell Neurosci 2015;9:391. PMID: 26500495. DOI. 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.
  4. Kamath et al.: Elevated levels of homocysteine compromise blood-brain barrier integrity in mice. Blood 2006;107:591-3. PMID: 16189268. DOI. Elevated levels of plasma homocysteine (Hcy) correlate with increased risk of cardiovascular and Alzheimer diseases. We studied the effect of elevated Hcy on the blood-brain barrier (BBB) to explore the possibility of a vascular link between the 2 diseases. On a hyperhomocysteinemic diet, cystathionine beta-synthase (Cbs)-heterozygous mice develop hyperhomocysteinemia. Intravital microscopy analysis of the mesenteric venules showed that leukocyte rolling velocity was markedly decreased and numbers of adherent cells were increased in the mutant mice. This was due at least in part to increased expression of P-selectin. BBB permeability was measured by Evans blue dye permeation and was found to be 25% greater in the Cbs(+/-) cortex compared with wild-type controls. Our study suggests an important toxic effect of elevated Hcy on brain microvessels and implicates Hcy in the disruption of the BBB.