Cysteinyl Leukotrienes as Potential Pharmacological Targets for Cerebral Diseases

Table 1

The neuroprotective effects of drugs acting on CysLT pathway in CNS disorders.

Brain ischemia
Model	Drug class	Molecule	Effect	Reference
Transient MCAO in gerbils	5-LOX inhibitor	AA-861	↓ neuronal death	[70, 71]
Transient MCAO; in rats	5-LOX inhibitor	Minocycline	↓ ischemic injuries, IgG exudation, and neutrophils; and macrophage/microglia accumulation	[83]
Permanent MCAO in rats	FLAP inhibitor	MK-886	↓ acute infarct size	[72]
Permanent MCAO in rats	5-LOX inhibitor	Zileuton	↓ edema, infarct volume, neurological deficits, MPO; activity, lipid peroxidation levels, inflammatory reaction,; and apoptosis	[73–75]
OGD in rats astrocytes	FLAP inhibitor	MK-886	↓ astrocyte proliferation and death	[29]
OGD in rats astrocytes	5-LOX inhibitor	Zileuton	↓ astrocyte proliferation and death	[29]
OGD in rats astrocytes	5-LOX inhibitor	Caffeic acid	↓ astrocyte proliferation and death	[29]
Transient MCAO in rats and mice	CysLTR-1 antagonist	Pranlukast	↓ neurological deficits, infarct volume, BBB disruption,; neuron loss in the ischemic core, astrocyte proliferation in the boundary zone, and ischemia-induced glial scar formation; ↑ motor-sensory recovery	[15, 65, 68, 78]
Permanent MCAO in rats and mice	CysLTR-1 antagonist	Pranlukast	↓ neurological deficits, infarct volume, edema,; BBB disruption, neuron degeneration, and MPO-positive; neutrophil accumulation	[49]
Transient MCAO in rats and mice	CysLTR-1 antagonist	Montelukast	↓ infarct size, brain atrophy, neuron loss, behavioural; dysfunction, oxidative stress, inflammation, release; of glutamate, apoptosis, and lactate dehydrogenase activity	[80, 81]
Permanent MCAO in rats and mice	CysLTR-1 antagonist	Montelukast	↓ infarct volume, brain edema, neuron density,; and neurological deficits	[6, 79]
Neonatal hypoxic-ischemic brain damage	CysLTR-1 antagonist	Montelukast	↓ ischemic cerebral and nerve damage; ↑ behavior recovery of chronic ischemic brain damage	[82]
OGD in rats astrocytes	CysLTR-1 antagonist	Montelukast	↓ astrocyte proliferation	[29]
Transient MCAO in rats	CysLTR-2 antagonist	HAMI 3379	↓ neurological deficits, lesion volume, edema,; and neuronal degeneration and loss	[50, 69]
OGD in PC12 cell	CysLTR-1/CysLTR-2 dual antagonist	Bay-u9773	↓ apoptosis	[62]
OGD in rats astrocytes	CysLTR-2 antagonist	Bay CysLT2	↓ astrocyte death	[29]
OGD in rats astrocytes	CysLTR-1/CysLTR-2 dual antagonist	Bay-u9773	↓ astrocyte proliferation and death	[29]
Alzheimer’s disease
Model	Drug class	Molecule	Effect	Reference
Tg2576 mice	FLAP inhibitor	MK-591	↓ Aβ peptide (Aβ) deposition, γ-secretase complex,; neuroinflammation, and microglia and astrocytes activation	[120]
N2A-APPswe cells	FLAP inhibitor	MK-591	↓ Aβ peptide (Aβ) deposition, γ-secretase complex	[120]
Tg2576 mice	5-LOX inhibitor	Zileuton	↓ Aβ peptide (Aβ) deposition, γ-secretase complex	[121]
N2A-APPswe cells	5-LOX inhibitor	Zileuton	↓ Aβ peptide (Aβ) deposition, γ-secretase complex	[121]
3xTg mice	FLAP inhibitor	MK-591	↓ Aβ peptide (Aβ) deposition, behavioural deficits,; neuroinflammation, and microglia and astrocytes activation	[127]
Tg2576 mice	FLAP inhibitor	MK-591	↓ brain tau phosphorylation	[128]
Rat hippocampal neurons treated with Aβ1–42	5-LOX inhibitors	NDGA,; AA-861	Prevention of neuronal injury and accumulation of ROS	[129]
Microinfusion of Aβ1–42	CysLTR-1 antagonist	Montelukast	Improvement of memory impairment via inhibiting; neuroinflammation and apoptosis	[125]
Mouse cortical neurons treated with Aβ1–42	CysLTR-1 antagonist	Pranlukast	Reverse Aβ1–42-induced cognitive deficit and AD features	[130]
Microinfusion of Aβ1–42	CysLTR-1 antagonist	Pranlukast	↓ apoptosis	[130]
Mouse neurons treated with Aβ1–42	CysLTR-1 antagonist	Montelukast	↓ proinflammatory factors and the apoptosis-related proteins	[131]
Microinfusion of Aβ1–42	CysLTR-1 antagonist	Pranlukast	Improvement of memory impairment via inhibiting; neuroinflammation and apoptosis	[132]
Parkinson’s disease
Model	Drug class	Molecule	Effect	Reference
MPTP-treated mice	FLAP inhibitor	MK-866	↓ toxicity of dopaminergic neurons; ↑ [^3H]-dopamine up-take	[137]
MPP^+ treated SH-SY5Y cell line	FLAP inhibitor	MK-866	↓ toxicity of dopaminergic neurons; ↑ [^3H]-dopamine uptake and cell survival	[137]
LPS-treated mice	5-LOX/COX inhibitor	Phenidone	↓ oxidative stress, microglial activation, and demise of the; nigral dopaminergic neurons	[139]
LPS-treated mice	5-LOX inhibitor	Caffeic acid	↓ dopaminergic neurodegeneration and microglia activation	[139]
Multiple sclerosis/experimental autoimmune encephalomyelitis
Model	Drug class	Molecule	Effect	Reference
PLP-induced EAE mice	5-LOX inhibitor	Zileuton	Delay of the onset and reduction of cumulative EAE severity	[152]
MOG-induced EAE mice	5-LOX inhibitor	Zileuton	Delay of the onset and reduction of cumulative EAE severity	[153]
Cuprizone-treated mice	FLAP inhibitor	MK-886	↓ axonal damage, motor deficits, and neuroinflammation	[149]
MOG-induced EAE mice	CysLTR-1 antagonist	Zafirlukast	↓ CNS infiltration of inflammatory cells and symptoms of EAE	[148]
MOG-induced EAE mice	CysLTR-1 antagonist	Montelukast	↓ demyelination, leukocyte infiltration, secretion of IL-17,; permeability of the BBB, chemotaxis of T cells, and severity of EAE	[148]
MOG-induced EAE mice	Dual inhibitor of LOX/COX pathway	Flavocoxid	↓ CNS infiltration of inflammatory cells, infiltration and differentiation of Th1+ and Th17+ cells, and symptoms of EAE	[154]
Epilepsy
Model	Drug class	Molecule	Effect	Reference
Kainic acid rat model	5-LOX/COX inhibitor	Phenidone	↓ seizure activity, neurotoxic signs, neuronal loss,; lipid peroxidation, and protein oxidation	[160, 166]
Kainic acid rat model	5-LOX/COX inhibitor	BW755C	↓ severity of seizures and neurotoxicity	[167]
Pilocarpine rat model	5-LOX inhibitor	Zileuton	↓ spike–wave discharges	[168]
PTZ-mice model	CysLTR-1 antagonist	Montelukast	↓ recurrent seizures, frequency of daily seizures,; BBB disruption, leukocyte migration, and mean; amplitude of EEG recordings during seizures.; ↑ increased the latency to generalized seizures	[162, 163]
PTZ-mice model	γ-Glutamyl; transpeptidase inhibitor	1,2,3,4, Tetrahydroisoquinoline	↓ kindled seizures and frequency of daily seizures	[162]
Pilocarpine mice model	CysLTR-1 antagonist	Montelukast	↓ kindled seizures and frequency of; daily seizures	[162]
Pilocarpine mice model	γ-Glutamyl; transpeptidase inhibitor	1,2,3,4, Tetrahydroisoquinoline	↓ recurrent seizures and frequency of daily seizures	[162]
Electrically kindled; seizure mice	CysLTR-1 antagonist	Montelukast	↓ recurrent seizures and frequency of daily seizures	[162]
Electrically kindled; seizure mice	γ-Glutamyl; transpeptidase inhibitor	1,2,3,4, Tetrahydroisoquinoline	↓ recurrent seizures and frequency of daily seizures	[162]
PTZ-mice model	CysLTR-1 antagonist	Pranlukast	↓ seizure susceptibility and mean; amplitude of; ictal EEG recordings	[163]
PTZ-mice model	CysLTR-1/CysLTR-2 dual antagonist	Bay- u9773	↑ increased the latency to generalized seizures; ↓ mean amplitude of EEG recordings during seizures	[163]
Patients with intractable partial seizures	CysLTR-1 antagonist	Pranlukast	↓ seizure frequencies, leakage of; proinflammatory; cytokines into CNS, and extravasation; of leucocytes,; normalizing serum MMP-9	[22]