Novel fatty acid-binding protein 3 ligand inhibits dopaminergic neuronal death and improves motor and cognitive impairments in Parkinson's disease model mice.

The main symptom of Parkinson's disease (PD) is motor dysfunction and remarkably approximately 30-40% of PD patients exhibit cognitive impairments. Recently, we have developed MF8, a heart-type fatty acid-binding protein (FABP3)-specific ligand, which can inhibit α-synuclein (α-syn) oligomerization induced by arachidonic acid in FABP3 overexpressing neuro2A cells. The present study aimed to determine whether MF8 attenuates dopaminergic neuronal death and motor and cognitive impairments in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice model. MF8 can penetrate the blood-brain barrier and its peak brain concentration (21.5 ± 2.1 nM) was achieved 6 h after the oral administration (1.0 mg/kg). We also compared its effects and pharmacological action with those of L-DOPA (3,4-dihydroxy-l-phenylalanine). PD model mice were developed by administering MPTP (25 mg/kg, i.p.) once a day for five consecutive days. Twenty-four hours after the final MPTP injection, mice were administered MF8 (0.3, 1.0 mg/kg, p.o.) or L-DOPA (25 mg/kg, i.p.) once a day for 28 consecutive days and subjected to behavioral and histochemical studies. MF8 (1.0 mg/kg, p.o.), but not L-DOPA, inhibited the dopaminergic neuronal death in the ventral tegmental area and the substantia nigra pars compacta region of the MPTP-treated mice. MF8 also improved both, motor and cognitive functions, while L-DOPA ameliorated only motor dysfunction. Taken together, our results showed that MF8 attenuated the MPTP-induced dopaminergic neuronal death associated with PD pathology. We present MF8 as a novel disease-modifying therapeutic molecule for PD, which acts via a mechanism different from that of L-DOPA.

Enhancement of ATP production ameliorates motor and cognitive impairments in a mouse model of MPTP-induced Parkinson's disease.

Approximately 30-40% of patients with Parkinson's disease (PD) exhibit cognitive impairments. However, there are currently no clinically effective drugs for the treatment of cognitive impairment in patients with PD. Previous studies have suggested that mitochondrial dysfunction such as decreased adenosine triphosphate (ATP) production triggers dopaminergic neurodegeneration in patients with PD and that mitochondria represent a potential target for the development of novel treatments for preventing PD. Therefore, in the present study, we investigated the cognition-enhancing effects of ethyl pyruvate (EP) and 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl) piperazine dihydrochloride (SA4503) in mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism. PD model mice were generated via treatment with MPTP (25 mg/kg, i.p.) once a day for 5 consecutive days. Twenty-four hours after the final injection of MPTP, mice were intraperitoneally injected with EP (25, 50, 100 mg/kg) or SA4503 (1 mg/kg) once a day for 4 weeks. Chronic administration of EP (100 mg/kg i.p.) or SA4503 (1 mg/kg, i.p.) improved both motor deficits and cognitive impairments in MPTP-treated mice. Furthermore, treatment with EP or SA4503 attenuated decreases in the levels of ATP and tyrosine hydroxylase (TH) in the substantia nigra pars compacta (SNpc)/ventral tegmental area (VTA), striatum, and hippocampal CA1 region. Administration of EP or SA4503 protected the dopaminergic neurons from MPTP-induce toxicity and restored the dopamine levels in the striatum. Elevated 4-hydroxy-2-nonenal- (4-HNE-) and nitrotyrosine-reactive protein levels induced by MPTP-treatment were suppressed by EP or SA4503 treatment in the SNpc-VTA, striatum, and hippocampal CA1 region. These observations suggest that EP and SA4503 attenuate cognitive impairments and motor dysfunction in mice with MPTP-induced PD.

Pharmacological properties of SAK3, a novel T-type voltage-gated Ca2+ channel enhancer.

T-type voltage-gated Ca2+ channels (T-VGCCs) function in the pathophysiology of epilepsy, pain and sleep. However, their role in cognitive function remains unclear. We previously reported that the cognitive enhancer ST101, which stimulates T-VGCCs in rat cortical slices, was a potential Alzheimer's disease therapeutic. Here, we introduce a more potent T-VGCC enhancer, SAK3 (ethyl 8'-methyl-2',4-dioxo-2-(piperidin-1-yl)-2'H-spiro[cyclopentane-1,3'-imidazo [1,2-a]pyridin]-2-ene-3-carboxylate), and characterize its pharmacological properties in brain. Based on whole cell patch-clamp analysis, SAK3 (0.01-10 nM) significantly enhanced Cav3.1 currents in neuro2A cells ectopically expressing Cav3.1. SAK3 (0.1-10 nM nM) also enhanced Cav3.3 but not Cav3.2 currents in the transfected cells. Notably, Cav3.1 and Cav3.3 T-VGCCs were localized in cholinergic neurve systems in hippocampus and in the medial septum. Indeed, acute oral administration of SAK3 (0.5 mg/kg, p.o.), but not ST101 (0.5 mg/kg, p.o.) significantly enhanced acetylcholine (ACh) release in the hippocampal CA1 region of naïve mice. Moreover, acute SAK3 (0.5 mg/kg, p.o.) administration significantly enhanced hippocampal ACh levels in olfactory-bulbectomized (OBX) mice, rescuing impaired memory-related behaviors. Treatment of OBX mice with the T-VGCC-specific blocker NNC 55-0396 (12.5 mg/kg, i.p.) antagonized both enhanced ACh release and memory improvements elicited by SAK3 administration. We also observed that SAK3-induced ACh releases were significantly blocked in the hippocampus from Cav3.1 knockout (KO) mice. These findings suggest overall that T-VGCCs play a key role in cognition by enhancing hippocampal ACh release and that the cognitive enhancer SAK3 could be a candidate therapeutic in Alzheimer's disease.