Effects of creatine treatment on survival and differentiation of GABA‐ergic neurons in cultured striatal tissue

Abstract

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder, characterized by a prominent loss of GABA-ergic medium-sized spiny neurons in the caudate putamen. There is evidence that impaired energy metabolism contributes to neuronal death in HD. Creatine is an endogenous substrate for creatine kinases and thereby supports cellular ATP levels. This study investigated the effects of creatine supplementation (5 mM) on cell survival and neuronal differentiation in striatal cultures. Chronic creatine treatment resulted in significant increased densities of GABA-immunoreactive (-ir) neurons, although total neuronal cell number and general viability were not affected. Similar effects were seen after short-term treatment, suggesting that creatine acted as a differentiation factor. Inhibitors of transcription or translation did not abolish the creatine-mediated effects, nor did omission of extracellular calcium, whereas inhibition of mitogen-activated protein kinase and phosphatidylinositol-3-kinase significantly attenuated the creatine induced increase in GABA-ir cell densities. Creatine exhibited significant neuroprotection against toxicity instigated either by glucose-and serum deprivation or addition of 3-nitropropionic acid. In sum, the neuroprotective properties in combination with promotion of neuronal differentiation suggest that creatine has potential as a therapeutic drug in the treatment of neurodegenerative diseases, like HD.

In sickness and in health: the widespread application of creatine supplementation

“…In vitro studies mimicking Parkinson's disease revealed that Cr has protective effects against neurotoxic insults (Andres et al 2005). A large RCT corroborated such promising observations, indicating that Cr supplementation is not futile in Parkinson's patients.…”

Creatine affects in vitro electrophysiological maturation of neuroblasts and protects them from oxidative stress

“…It is worth considering that GABA receptor activity plays an important role during brain development, participating in neuron differentiation, migration, dendritic maturation, and modeling of neuronal circuitry (for an extensive review see Represa and Ben-Ari, 2005). Moreover, in vitro Cr supplementation has been observed to readdress neuron differentiation toward a GABA-ergic phenotype in striatal (Andres et al, 2005) and spinal cord (Ducray et al, 2007) cell cultures.…”

Prevalence of Creatine Deficiency Syndromes in Children With Nonsyndromic Autism

“…23 In cultured cells, creatine supplementation protects rat hippocampal neurons against glutamate and amyloid β-peptide toxicity. 24 Data using human fetal striatal and mesencephalic tissue identified creatine as a potent natural survival and neuroprotective factor for γ-aminobutyric acid-ergic neurons in a model for Huntington disease 25 and of dopaminergic neurons in a model for Parkinson disease. 26 Recent interest in routine screening children with ASD for inborn errors of metabolism, and in particular CDS, 27,28 raises the question of how many children with ASD could potentially benefit from such screening.…”