Protective Role for Type 4 Metabotropic Glutamate Receptors against Ischemic Brain Damage

Abstract

We examined the influence of type 4 metabotropic glutamate (mGlu4) receptors on ischemic brain damage using the permanent middle cerebral artery occlusion (MCAO) model in mice and the endothelin-1 (Et-1) model of transient focal ischemia in rats. Mice lacking mGlu4 receptors showed a 25% to 30% increase in infarct volume after MCAO as compared with wild-type littermates. In normal mice, systemic injection of the selective mGlu4 receptor enhancer, N-phenyl-7-(hydroxyimino) cyclopropa[b]chromen-1a-caboxamide (PHCCC; 10 mg/kg, subcutaneous, administered once 30 minutes before MCAO), reduced the extent of ischemic brain damage by 35% to 45%. The drug was inactive in mGlu4 receptor knockout mice. In the Et-1 model, PHCCC administered only once 20 minutes after ischemia reduced the infarct volume to a larger extent in the caudate/putamen than in the cerebral cortex. Ischemic rats treated with PHCCC showed a faster recovery of neuronal function, as shown by electrocorticographic recording and by a battery of specific tests, which assess sensorimotor deficits. These data indicate that activation of mGlu4 receptors limit the development of brain damage after permanent or transient focal ischemia. These findings are promising because selective mGlu4 receptor enhancers are under clinical development for the treatment of Parkinson's disease and other central nervous system disorders.

A Potent and Selective Metabotropic Glutamate Receptor 4 Positive Allosteric Modulator Improves Movement in Rodent Models of Parkinson's Disease

“…The potential therapeutic utility may extend beyond PD. Neuroprotection with PHCCC has been reported in cerebral ischemia models in mice (Moyanova et al, 2011). Studies with PHCCC have suggested an anxiolytic effect of 4-PAMs (Stachowicz et al, 2004(Stachowicz et al, , 2006, an effect that we have also observed with ADX88178 (B. Campo, S. E. Browne, F. Girard, F. Hess, J. Uslaner, E. Le Poul, and I. J. Reynolds, unpublished work).…”

The Application Of Permanent Middle Cerebral Artery Ligation in the Mouse

“…However, it is possible to obtain subcortical lesions if the MCA is ligated proximal to the lenticulostriate branch. The stroke volumes after MCA ligation might vary from 10mm³ to 35mm³ 19,23 . The stroke volumes calculated with TTC staining in Moyanova et al 19 are between 10mm³ to 22mm³ while the stroke volumes determined from MRI images in Filiano et al 23 are between 20mm³ to 35mm³.…”

“…The stroke volumes after MCA ligation might vary from 10mm³ to 35mm³ 19,23 . The stroke volumes calculated with TTC staining in Moyanova et al 19 are between 10mm³ to 22mm³ while the stroke volumes determined from MRI images in Filiano et al 23 are between 20mm³ to 35mm³. The possible reason for these differences maybe the exact location of the ligation and the different methods used to measure the stroke volumes.…”

Activation of Type 4 Metabotropic Glutamate Receptor Attenuates Oxidative Stress-Induced Death of Neural Stem Cells with Inhibition of JNK and p38 MAPK Signaling

“…*P < 0.05 versus H 2 O 2 group. mGluR4 activation, which was considered to protect mature neurons against excitotoxic cell death and maintain the homeostasis of extracellular glutamate levels [8,9], enhance the antioxidant capacity of NSCs, which may promote the survival of NSCs in hostile surrounding microenvironment of disease conditions. H 2 O 2 -induced neuronal apoptosis is a mixture response and involved multiple apoptotic pathways, such as activity of caspase cascades and perturbation of Bcl-2/Bax balance [18,47].…”

“…Similar to its counterparts in group III mGluRs (mGluR4, 6, 7, and 8), mGluR4 is preferentially localized in presynaptic terminals and is thought to mediate the presynaptic depression of glutamatergic synaptic transmission, most likely through inhibition of glutamate release [7]. In addition, selective activation of mGluR4 also results in neuroprotection against excitotoxic insults in Parkinson's disease, ischemic stroke, and other CNS disorders [8][9][10][11][12]. Moreover, functional mGluR4 has been found to be expressed in embryonic stem cell-derived neural stem/progenitor cells and cerebellar granule cell neuroprecursors, and may play roles in inhibition, cell proliferation, and promotion of neuronal differentiation, although the underlying mechanisms have not been clarified [13][14][15].…”