Prevention and restoration of lactacystin‐induced nigrostriatal dopamine neuron degeneration by novel brain‐permeable iron chelators

Abstract

Dysfunction of the ubiquitin-proteasome system (UPS) and accumulation of iron in substantia nigra (SN) are implicated in the pathogenesis of Parkinson's disease (PD). UPS dysfunction and iron misregulation may reinforce each other's contribution to the degeneration of dopamine (DA) neurons. In the present study, we use a new brain-permeable iron chelator, VK-28 [5-(4-(2-hydroxyethyl) piperazin-1-yl (methyl)-8-hydroxyquinoline], and its derivative M30 [5-(N-methyl-N-propargyaminomethyl)-8-hydroxyquinoline] in vivo to test their neuroprotective and neurorestorative properties against proteasome inhibitor (lactacystin) -induced nigrostriatal degeneration. Bilateral microinjections of lactacystin (1.25 microg/side) into the mouse medial forebrain bundle were performed. Administration of VK-28 (5 mg/kg, once a day) or M30 (5 mg/kg, once a day) was applied intraperitoneally 7 days before or after the lactacystin microinjection until the mice were sacrificed 28 days after microinjection. We found that VK-28 and M30 both significantly improved behavioral performances and attenuated lactacystin-induced DA neuron loss, proteasomal inhibition, iron accumulation, and microglial activation in SN. In addition, M30 restored the Bcl-2 level, which was suppressed after lactacystin injection. These findings suggest that brain-permeable iron chelators can improve DA neuron survival under UPS impairment. Furthermore, M30, a derivative of VK-28 and neuroprotective agent rasagiline, may serve as a better neuroprotective therapy for PD.

Neuroprotection of desferrioxamine in lipopolysaccharide-induced nigrostriatal dopamine neuron degeneration

“…Wet ventral midbrains were weighed and then digested in concentrated hydrochloric acid. Tissue iron concentrations (nmol/g) were determined spectrophotometrically using the kit from DCL (Diagnostic Chemicals Ltd., Oxford, CT, USA) in a modified microtiter plate assay as previously described by Zhu et al (14).…”

“…The major mechanism of iron-mismanagement was related to increased iron uptake by DMT1, Tf/TfR2 and Lf/ LfR (5-7), decreased iron export by Fp1 and Cp (8,9), and iron storage misregulation by ferritin and lysosome (10)(11)(12). Application of iron chelation demonstrated a protective effect against DA neuron degeneration in PD animal models induced by N-methyl-4-pheny-1, 2, 3, 6-tetrahydropyridine (MPTP) and lactacystin (4,(13)(14)(15).…”

Redox Control of Prion and Disease Pathogenesis

“…The change in conformation of PrP C to the PrP Sc form is likely to compromise the normal protective function of PrP C , resulting in neurotoxicity. such as AD, multiple sclerosis, PD, tardive dyskinesia, Pick's disease, HD, Hallervorden-Spatz disease, Friedreich's ataxia, and aceruloplasminemia (10,11,68,(250)(251)(252)(253). In addition to iron excess, a deficiency of this metal is equally harmful and can result in compromised motor and cognitive function, in addition to other manifestations of anemia (15,133).…”

“…A similar reduction of PrP Sc levels in vivo may prove useful in decreasing PrP Sc load, although optimal iron chelators that are nontoxic at therapeutic doses and can cross the blood-brain barrier effectively have not been developed. Studies in MPTP mouse models of Parkinson disease report significant benefit from the concomitant administration of blood-brain barrier-permeable iron chelator VK-28 [5-(4-(2-hydroxyethyl) piperazin-1-yl (methyl)-8-hydroxyquinoline] and its derivative M30 [5-(Nmethyl-N-propargyaminomethyl)-8-hydroxyquinoline], providing direct evidence for the involvement of iron in disease pathogenesis (253). However, the applicability of these compounds in prion disease-associated neurotoxicity is yet to be investigated.…”

Multifunctional Neuroprotective Derivatives of Rasagiline as Anti-Alzheimer's Disease Drugs

“…Indeed, recent studies have shown a significant neuroprotective action of M-30 against MPTP neurotoxicity 73 or the proteasome inhibitor, lactacystin, in mice. 74 In addition, M-30 is a potent radical scavenger and brain selective irreversible MAO-A and MAO-B inhibitor, with little inhibition of peripheral MAO (liver and small intestine) that limits the potentiation of cardiovascular effect of tyramie ("cheese reaction"), 75 indicating that M-30 may possess antidepressant activity, and thus can be implicated for treatment AD.…”