NR2B-containing NMDA receptors promote the neurotoxic effects of 3-nitropropionic acid but not of rotenone in the striatum.
Decreased activity of mitochondrial complex I and II is implicated in the pathophysiology of progressive supranuclear palsy (PSP) and Huntington's disease (HD), respectively. Both disorders preferentially affect the nucleus striatum, a brain area particularly vulnerable to excitotoxic damage. To gain insights into the pathophysiology of neuronal degeneration during PSP and HD, here we studied the possible interplay between excitatory transmission and mitochondrial complex I and II inhibition in the development of striatal damage. By using in vitro neurophysiological recordings and cell swelling measures in corticostriatal slices, we found that stimulation of NMDA receptors significantly contributed to the neurotoxic effects of 3-nitropropionic acid (3-NP) but not of rotenone, selective inhibitors of mitochondrial complex II and I, respectively. We also found that blockade of a subset of NMDA receptors containing the NR2B subunit was sufficient to protect the striatum from the injurious effects of 3-NP, an effect unrelated to the prevention of membrane excitation by NMDA receptor stimulation. Pharmacological inhibition of dopamine receptors, conversely, failed to modulate both rotenone- and 3-NP-induced neuronal damage. Our results indicate that the cellular mechanisms leading to striatal neuronal death are different following inhibition of distinct mitochondrial complexes of the respiratory chain, implying that neuroprotective strategies in PSP and HD must significantly differ.
Centonze
Diego
D
Clinica Neurologica, Dipartimento di Neuroscienze, Università Tor Vergata, 00133 Rome, Italy. centonze@uniroma2.it
Prosperetti
Chiara
C
Barone
Ilaria
I
Rossi
Silvia
S
Picconi
Barbara
B
Tscherter
Anne
A
De Chiara
Valentina
V
Bernardi
Giorgio
G
Calabresi
Paolo
P
D000200:Action Potentials / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D002452:Cell Count / Q000379:methods; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects; D009498:Neurotoxins / Q000494:pharmacology*; D009574:Nitro Compounds / Q000494:pharmacology*; D011422:Propionates / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D012402:Rotenone / Q000494:pharmacology*
D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; C121001:NR2B NMDA receptor; D009498:Neurotoxins; D009574:Nitro Compounds; D011422:Propionates; D016194:Receptors, N-Methyl-D-Aspartate; D012402:Rotenone; C015392:3-nitropropionic acid