Homocysteine potentiates seizures and cell loss induced by pilocarpine treatment.
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.
Baldelli
Enrica
E
Dipartimento di Scienze Biomediche, Università di Modena e Reggio Emilia, Via Campi 287, Modena, Italy.
Leo
Giuseppina
G
Andreoli
Nicola
N
Fuxe
Kjell
K
Biagini
Giuseppe
G
Agnati
Luigi F
LF
D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D004833:Epilepsy, Temporal Lobe / Q000097:blood / Q000473:pathology; D005452:Fluoresceins; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D006710:Homocysteine / Q000097:blood / Q000494:pharmacology; D006801:Humans; D008297:Male; D009410:Nerve Degeneration / Q000139:chemically induced*; D009930:Organic Chemicals / Q000378:metabolism; D010862:Pilocarpine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013226:Status Epilepticus / Q000097:blood / Q000139:chemically induced / Q000473:pathology
D016229:Amyloid beta-Peptides; D005452:Fluoresceins; D009930:Organic Chemicals; C435731:fluoro jade; D010862:Pilocarpine; D006710:Homocysteine