Homocysteine Potentiates Seizures and Cell Loss Induced by Pilocarpine Treatment

Abstract

Patients affected by recurrent seizures frequently present increased homocysteine plasma levels in consequence of treatment with antiepileptic drugs. Homocysteine is proconvulsant and can affect the response to antiepileptic drugs. In addition, high homocysteine plasma levels represent a risk factor for cardiovascular and neurodegenerative diseases. To better define the role of increased homocysteine in epilepsy, we analyzed the effects of homocysteine pretreatment in the pilocarpine model of status epilepticus (SE), which is used to mimic temporal lobe epilepsy (TLE) in rodents. Precisely, we investigated whether a moderate hyperhomocysteinemia, unable to cause seizures, could sensitize rats to pilocarpine and cooperate in inducing brain lesions. We found that a subthreshold dose of pilocarpine (200 mg/kg) is sufficient to induce SE in the majority (approximately 90%) of rats pretreated with homocysteine for 2 weeks, whereas only 40% of saline-treated controls developed SE following the same pilocarpine dose. Furthermore, homocysteine pretreatment led to a significant increase in neuronal cell loss evaluated by counting toluidine blue-stained or Fluoro-Jade-positive cells in hippocampal and parahippocampal regions. Pilocarpine augmented amyloid beta expression in both animal groups. However, pretreatment with homocysteine favored the intraneuronal fibrillar conformation of amyloid beta, thus promoting neurodegeneration. These findings indicate that increased homocysteine levels enhance seizure activity and neurodegeneration in pilocarpine-treated rats and suggest that similar detrimental effects may occur in patients affected by TLE.

Role of Homocysteine in the Ischemic Stroke and Development of Ischemic Tolerance

“…In agreement with this finding it was suggested that systemic administration of Hcy at high doses provokes convulsive attacks in mice and it was proposed that similar detrimental effects can be manifested in patients suffering from temporal lobe epilepsy (Baldelli et al, 2010). Consequently, the Hcy-derived chemical reactive metabolites are thought to have an important role in Hcy-induced seizures.…”

The emerging role of DNA methylation in epileptogenesis

“…Intriguingly, increased Adk expression is frequently observed in chronic epileptic tissue, accounting for continuous removal of adenosine and shifting chemical equilibrium toward AMP synthesis (Boison, 2008). Disturbances in folate metabolism (e.g., low‐folate diet or MTHFR mutations/reduced enzymatic activity) have been associated with increased CSF levels in homocysteine, a proconvulsant, and seizures (Goyette et al., 1995; Ono et al., 2000; Chen et al., 2001; Baldelli et al., 2010). AMP, adenosine monophosphate; ADK, adenosine kinase; DNMTs, DNA methyltransferases; MAT, methionine adenosyltransferase; MTHFR, methylene tetrahydrofolate reductase; 5‐MTHF, 5′ methylene tetrahydrofolate; SAHH, S‐adenosylhomocysteine hydrolase; THF, tetrahydrofolate.…”

“…Of interest, there is a considerable phenotypic overlap of severe MTHFR deficiency with Angelman syndrome and Rett syndrome, both of which are autism spectrum disorders with high incidence of seizures. Furthermore, the 677C>T MTHFR variant, which causes mild reduction in MTHFR activity, is a genetic risk factor for seizures or epilepsy (Ono et al., 2000; Baldelli et al., 2010). Cerebral folate deficiency (CFD) syndrome is a pediatric neurologic disorder characterized by low cerebrospinal fluid (CSF) levels of 5‐MTHF.…”

Branch Retinal Artery Occlusion Associated with Hyperhomocysteinemia: Case Report

“…Further, some studies have demonstrated that hyperhomcysteinemia might be involved in the pathophysiology of many neuropsychiatric disorders, including brain atrophy, epilepsy, and Alzheimer's disease [15][16][17][18]. But homocysteinemia-lowering therapies from an early age are it effective at preventing neuropsychiatric disorders?…”