Glycine Administration Alters MAPK Signaling Pathways and Causes Neuronal Damage in Rat Brain: Putative Mechanisms Involved in the Neurological Dysfunction in Nonketotic Hyperglycinemia

Abstract

High glycine (GLY) levels have been suggested to induce neurotoxic effects in the central nervous system of patients with nonketotic hyperglycinemia (NKH). Since the mechanisms involved in the neuropathophysiology of NKH are not totally established, we evaluated the effect of a single intracerebroventricular administration of GLY on the content of proteins involved in neuronal damage and inflammatory response, as well as on the phosphorylation of the MAPK p38, ERK1/2, and JNK in rat striatum and cerebral cortex. We also examined glial fibrillary acidic protein (GFAP) staining, a marker of glial reactivity. The parameters were analyzed 30 min or 24 h after GLY administration. GLY decreased Tau phosphorylation in striatum and cerebral cortex 30 min and 24 h after its administration. On the other hand, synaptophysin levels were decreased in striatum at 30 min and in cerebral cortex at 24 h after GLY injection. GLY also decreased the phosphorylation of p38, ERK1/2, and JNK 30 min after its administration in both brain structures. Moreover, GLY-induced decrease of p38 phosphorylation in striatum was attenuated by N-methyl-D-aspartate receptor antagonist MK-801. In contrast, synuclein, NF-κB, iκB, inducible nitric oxide synthase and nitrotyrosine content, and GFAP immunostaining were not altered by GLY infusion. It may be presumed that the decreased phosphorylation of MAPK associated with alterations of markers of neuronal injury induced by GLY may contribute to the neurological dysfunction observed in NKH.

Integrative Approach to Predict Severity in Nonketotic Hyperglycinemia

“…This results in excitotoxicity via NMDA receptor overstimulation, induces oxidative stress and bioenergetic dysfunction, and alters mitogen-activated protein kinase signaling pathways in animal models. [36][37][38][39] The latter was also observed in different models of depression 40,41 and autism. 42 An excessive increase of glycine in the synaptic cleft can result in activation of glycine receptors, an induction of NMDA receptor endocytosis, and depression of its response, 11 together with a downregulation of the glycine transporter (GlyT1).…”

“…Because NMDA receptors have a substantially higher affinity for glycine than glycine receptors, 34,35 elevated concentration of glycine has a predominantly excitatory action via NMDA receptors. This results in excitotoxicity via NMDA receptor overstimulation, induces oxidative stress and bioenergetic dysfunction, and alters mitogen‐activated protein kinase signaling pathways in animal models 36–39 . The latter was also observed in different models of depression 40,41 and autism 42 .…”

Use of Perampanel and a Ketogenic Diet in Nonketotic Hyperglycinemia: A Case Report

“…10 Glycine can be toxic to the CNS through oxidative stress and energy impairments. 11,12 The ketogenic diet may modify the neurotoxic cascade through NMDA receptor suppression and alterations in the energy cycle in the CNS, which may explain its efficacy in NKH. In addition, perampanel is also suspected to have neuroprotective effects against oxidative stress, 13 which may enhance the protective effects of the ketogenic diet after neurotoxic injury.…”

Neuroimaging Spectrum of Inherited Neurotransmitter Disorders

“…Glycine accumulation in the brain results in alteration of the MAPK signaling pathways and induces neuronal damage. 49 Glycine serves as an excitatory neurotransmitter on N-methyl-D-aspartate receptors in the cerebral hemispheres and cerebellum and as an inhibitory neurotransmitter in the brainstem and spinal cord. 50,51 The degradation product of glycine, 5,10-methylenetetrahydrofolate, is also an essential component for DNA synthesis.…”