Table 1.

Summary of In Vivo and In Vitro Trials of Catalytic Antioxidants in Neurodegenerative Disease

Disease	Compound	Treatment protocol	Results
Stroke/ischemia	AEOL 10150	60-min middle cerebral artery occlusion (MCAO) in mouse. Compound given intravenously (IV) 5 min after initiation of reperfusion	Microarray used to examine gene-expression changes; increased expression of inflammatory genes reduced by treatment (14)
	AEOL 10150 AEOL 10113	90-min MCAO in mouse. Compounds administered intracerebroventricularly (ICV) 90 min or 6 h after initiation of reperfusion	Both compounds reduced infarct size at 90 min. AEOL 10150 reduced infarct size when 2 administered 6 h after reperfusion (134)
	EUK-189 EUK-207	2-h Oxygen-glucose deprivation (OGD) and 2.5-h reoxygenation in hippocampal slices from 2-mo or p10 rats. Compound applied during OGD and reoxygenation	Compounds increased cell viability as assayed by LDH release and PI uptake. Compounds also reduced ATP depletion, blocked ROS production, and reduced ERK1/2 dephosphorylation. Increased cell survival related to ATP and ROS levels, not MEK/ERK or p38 pathways, or calpain activation (159)
	EUK-134 EUK-8	MCAO in rat. Compounds administered 3 h after focal ischemia	Reduced infarct size in dose-dependent manner. EUK-134 more effective, suggesting H2O2 important to injury (10)
	M40401	90-min MCAO in rat. Compound administered by injection 30 min before, 60 min into, or 90 min after initiation of MCAO	Infarct volume reduced only when compound administered before MCAO (136)
	M40401 M40403	Carotid ligation and 3-h 8% hypoxia in immature rats. Compounds administered 2 h before hypoxia/ischemia	M40403 and M40401 reduced infarct size (135)
	Carboxyfullerene	60-min MCAO in rat. Compound administered via IV or ICV 30 min before ischemia/reperfusion	ICV infusion reduced infarct size and prevented glutathione depletion and lipid peroxidation (90)
Alzheimer's disease	EUK-8 EUK-134 EUK-189	Primary rat cortical neurons, peroxynitrite generated by SIN-1	Compounds protect primary cortical neurons against cell death due to SIN-1 or H2O2 (126)
	EUK-189	Tg2567 (APP) mice. Compound administered via IP 3 times weekly from 90 to 300–400 days of age	Cataract severity reduced by treatment with EUK-189 (101)
	EUK-134	Primary rat microglial cells activated with LPS and INF-γ	EUK-134 reduced PGE2 production by activated microglia (6)
	EUK-8	Organotypic rat hippocampal slice cultures treated with Aβ (1-40 or 1-42). Compound added simultaneously	EUK-8 protected against Aβ-induced cell death and also blocked free radical accumulation and lipid peroxidation (17)
	EUK-8 EUK-134	Microglia purified from primary mixed glial cultures from 7-d rats. Activated with fibrillar Aβ(1–40)	Compounds blocked proliferation, and blocked the increase in TNF-α production by Aβ-activated microglia (76)
Parkinson's disease	EUK-134 EUK-189	Adult animals, N27 cell line, and primary mesencephalic cultures treated with paraquat. Compounds administered before paraquat exposure	Both compounds reduce cell death in paraquat-treated N27 cells and primary mesencephalic cultures. EUK-189 decreased SNpc dopaminergic cell death in response to paraquat in vivo (113)
	EUK-134	Primary dopaminergic neuronal cultures, exposed to MPP+ or 6-OHDA. Pretreated with EUK-134	Pretreatment with EUK-134 reduced neurotoxicity, and prevented nitration of tyrosine residues in tyrosine hydroxylase caused by MPP+ or 6-OHDA treatment (117)
	C3	Primary mesencephalic cultures treated with MPP+ or 6-OHDA	C3 rescued dopminergic neurons from 6-OHDA–meditated, and partially protected against MPP+–mediated cell death (94)
	MnTBAP	Murine dopaminergic cell line, treated with MPP+ or 6-OHDA	6-OHDA caused ROS-mediated JNK activation, which was attenuated by MnTBAP. MnTBAP reduced cell death induced by 6-OHDA, but not by MPP+ (26)
	AEOL 11207	MPTP mouse model of PD. Compound administered subcutaneously and orally	Compound protected against MPTP induced cell death, dopamine depletion, glutathione depletion, and 3-NT formation when administered SC or orally (89)
Epilepsy/excitotoxicity	EUK-134	Kainic acid (KA)-treated rats. Compound administered before KA treatment	Pretreatment with EUK-134 reduced protein nitration, AP-1 and NF-ϰB binding activity, spectrin proteolysis, and neuronal damage, but did not reduce latency or duration of seizures (125)
	MnTBAP	KA-treated rats. Compound administered via osmotic minipump starting 48 h before KA treatment	Pretreatment with MnTBAP improved neuronal survival, maintained aconitase activity, and reduced oxidative DNA damage, but did not affect behavioral seizures (87)
ALS	AEOL 10150	G93A mouse model of ALS, compound administered at symptom onset	Compound extended survival from onset up to threefold, increased motor neuron survival, and reduced astrogliosis and markers of oxidative stress (31)
	AEOL 10150 + PBA	G93A mouse model, of ALS, compounds administered alone or together at time of disease onset	AEOL 10150 increased survival by 11%, PBA by 13%, and combined treatment by 19%. Treatment reduced markers of oxidative stress, and increased expression of protective genes (115)
	EUK-8 EUK-134	G93A mouse model of ALS. Compound administered via IP injection starting at 60 days of age	Treatment reduced markers of oxidative stress and increased survival, but did not affect disease onset (78)
	C3	G93A mouse model of ALS. Compound continuously infused via osmotic minipump starting at 73 days of age	C3 treatment resulted in a 10-day delay in symptom onset, and 8-day improvement in survival (41)