1-aminocyclopentane-1-3-4-tricarboxylic-acid and Stroke

Our previous studies have shown that ACPT-I [(1S, 3R,4S)-1-aminocyclopentane-1,2,4-tricarboxylic acid], a blood-brain barrier permeable agonist of group III metabotropic glutamate (mGlu) receptors, was neuroprotective against middle cerebral artery occlusion/reperfusion (MCAO/R) in normotensive rats. Preclinical studies are typically performed on healthy animals, whereas stroke patients predominately exhibit comorbidities, such as hypertension; therefore, in the present study, we investigated the effect of ACPT-I in spontaneously hypertensive rats (SHR) after MCAO/R. We examined the potential neuroprotective action of ACPT-I (30 mg/kg) when administered during occlusion or reperfusion via the assessment of not only the brain infarction volume but also motor (CatWalk gait analysis and open field test) and sensorimotor (vibrissae-evoked forelimb-placing test) functions following MCAO/R. We determined that ACPT-I not only reduced the cortico-striatal infarction but also improved several gait parameters (run speed, run and stand durations, swing speed and stride length) and mobility when administered 30 min after the start of the occlusion or 30 min after the start of reperfusion. Moreover, the sensorimotor function was improved in hypertensive rats treated with ACPT-I during occlusion. In conclusion, the current findings provide further evidence for the neuroprotective effects of ACPT-I against ischemic damage. These findings may have clinical implications because hypertension is an important risk factor for ischemic stroke.

Topics: Animals; Brain; Brain Ischemia; Cyclopentanes; Essential Hypertension; Gait; Male; Neuroprotective Agents; Random Allocation; Rats, Inbred SHR; Receptors, Metabotropic Glutamate; Sensation; Stroke; Tricarboxylic Acids

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