1-aminocyclopentane-1-3-4-tricarboxylic-acid and Disease-Models--Animal

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

In the present study, we investigated the effect of ACPT-I [(1S, 3R,4S)-1-aminocyclopentane-1,2,4-tricarboxylic acid], a blood-brain-barrier permeable agonist of group III mGlu receptor, against oxygen-glucose deprivation (OGD)-evoked neuronal cell death in primary neuronal cell cultures and in the model of transient middle cerebral artery occlusion (MCAO) in rats. We found that ACPT-I (1-200 μM) in a concentration- and time-dependent way attenuated the OGD-induced neuronal cell damage, being also effective after a delayed application (30 min after OGD). The neuroprotective effects of ACPT-I were blocked by the group III mGlu receptor antagonist, (RS)-alpha-cyclopropyl-4-phosphonophenyl glycine (CPPG), and by the activator of cAMP-dependent PKA, 8-Bromo-cAMP, but not by an inhibitor of PI-3-K signaling pathway. Moreover, ACPT-I attenuated the OGD-induced calpain activity and glutamate release. In the in vitro study, we also demonstrated the neuroprotective potential of mGluR4 positive allosteric modulators (PAMs), PHCCC (30 μM) and VU0155041 (10 and 30 μM) and synergism in neuroprotective action of low concentrations of ACPT-I and mGluR4 PAMs suggesting an important role of mGluR4 activation in prevention of ischemic neuronal cell death. In the rat MCAO model, we demonstrated that ACPT-I (30 mg/kg) injected intraperitoneally either 30 min after starting MCAO or 30 min after beginning reperfusion not only diminished the infarction volume by about 30%, but also improved selected gait parameters (CatWalk analysis) and the mobility of animals in the open field test. In conclusion, our results indicate that ACPT-I may be not only neuroprotective against ischemic neuronal damage but may also diminish the postischemic functional deficits.

Topics: Animals; Brain Ischemia; Cells, Cultured; Cyclopentanes; Disease Models, Animal; Excitatory Amino Acid Agonists; L-Lactate Dehydrogenase; Male; Mice; Neurons; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; Stroke; Tricarboxylic Acids

Activation of group III metabotropic glutamate (mGlu) receptors has been recently highlighted as a potential approach in the treatment of Parkinson's disease (PD). This study evaluates the antiparkinsonian action of systemic administration of the broad-spectrum agonist of group III mGlu receptors, 1-aminocyclopentane-1,3,4-tricarboxylic acid (ACPT-I), and investigates its site of action within the basal ganglia circuitry. Acute injection of ACPT-I reverses haloperidol-induced catalepsy, an index of akinesia in rodents. In a rat model of early PD based on partial bilateral nigrostriatal lesions, chronic (2weeks) administration of ACPT-I is required to efficiently alleviate the akinetic deficit evidenced in a reaction time task. This treatment counteracts the post-lesional increases in the gene expression of cytochrome oxidase subunit I, a metabolic marker of neuronal activity, in the overall subthalamic nucleus and in the lateral motor part of the substantia nigra pars reticulata (SNr) but has no effect in the globus pallidus. Paradoxically, ACPT-I administration in sham animals impairs performance and induces overexpression of cytochrome oxidase subunit I mRNA in the lateral SNr, and has no effect in the subthalamic nucleus or globus pallidus. Altogether, our results provide new evidence for the antiparkinsonian efficiency of group III mGlu receptor agonism, point to the regulation of the overactive subthalamo-nigral connection as a main site of action in an early stage of PD and underline the complex interplay between these receptors and the dopaminergic system to regulate basal ganglia function in control and PD conditions.

Topics: Animals; Cyclopentanes; Disease Models, Animal; Excitatory Amino Acid Agonists; Male; Neural Pathways; Parkinsonian Disorders; Rats; Rats, Wistar; Receptors, Metabotropic Glutamate; Stereoisomerism; Substantia Nigra; Subthalamic Nucleus; Tricarboxylic Acids