Lamotrigine is neuroprotective in the energy deficiency model of MPTP intoxicated mice.
The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) inhibits the mitochondrial complex I of the respiratory chain. This results in ATP and ion homeostasis disturbances, which lead to selective death of the substantia nigra dopaminergic neurons. Well known as a Parkinson's disease model, the MPTP animal model also provides a potential paradigm of the energy deficiencies found in childhood. In these conditions, anticonvulsants may provide neuroprotection by limiting cellular energy consumption. We tested valproate, topiramate and lamotrigine in the MPTP mouse model. Dopamine transporter (DAT) density was assessed by quantitative autoradiography, tyrosine hydroxylase (TH) was evaluated by immunohistochemistry and dopamine (DA) levels by HPLC-ED whereas neuronal apoptosis was monitored through active caspase-3. Expectedly, the DAT density, TH immunoreactive neurons and DA content in the MPTP group were respectively reduced to 51%, 40% and 26% versus control animals. Unlike valproate and topiramate, lamotrigine provided a significant neuroprotection against MPTP in maintaining these levels at 99%, 74% and 58% respectively and reducing the induced apoptosis. Altogether, the data indicate that lamotrigine limits dopaminergic neuronal death in the substantia nigra and promotes striatal dendrites sprouting. Lamotrigine, a widely used and well-tolerated molecule in young patients, could represent a valuable adjuvant therapy in various energy deficiency conditions during childhood.
Lagrue
Emmanuelle
E
Inserm, U619, Tours, F-37000 France.
Chalon
Sylvie
S
Bodard
Sylvie
S
Saliba
Elie
E
Gressens
Pierre
P
Castelnau
Pierre
P
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000378:metabolism*; D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000378:metabolism* / Q000633:toxicity; D004734:Energy Metabolism; D005632:Fructose / Q000031:analogs & derivatives / Q000378:metabolism; D000077213:Lamotrigine; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000737:chemistry / Q000378:metabolism*; D009498:Neurotoxins / Q000378:metabolism* / Q000633:toxicity; D000077236:Topiramate; D014227:Triazines / Q000737:chemistry / Q000378:metabolism*; D014635:Valproic Acid / Q000378:metabolism
D000927:Anticonvulsants; D015259:Dopamine Agents; D018696:Neuroprotective Agents; D009498:Neurotoxins; D014227:Triazines; D000077236:Topiramate; D005632:Fructose; D014635:Valproic Acid; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000077213:Lamotrigine; D004298:Dopamine