in diseases of the central nervous system (Andres et al., 2008) (see also papers by Sullivan and by Hall in Appendix C).
Evidence of the importance of the creatine system for brain function comes from animal studies using creatine kinase knockout mice, which display significant reductions in hippocampal functioning and impairments in both learning and memory compared to non-genetically modified mice. Learning is further compromised in mice given a drug that competitively inhibits the creatine transporter and results in reductions of creatine pools in muscle and brain (Andres et al., 2008). In contrast, mice fed a diet supplemented with 1 percent creatine live longer, have less reactive oxygen species in their brains, and show better memory function than nonsupplemented littermates (Bender et al., 2008).
In humans, individuals born with errors in creatine synthesis or x-linked creatine transporter defects suffer from mental retardation, autistic behavior, severe language and speech impairments, epilepsy, and brain atrophy. In some individuals, the cognitive deficits resulting from these congenital errors can be improved, though not totally reversed, with chronic administration of large doses of creatine (Andres et al., 2008; Gualano et al., 2010).
Studies using nuclear magnetic resonance spectroscopy have shown that creatine supplementation increases brain levels of both creatine and phosphocreatine (Dechent et al., 1999; Pan and Takahashi, 2007). These increases in brain creatine may translate into improvements in cognitive behavior, particularly under stressful or compromised conditions. For example, young men given creatine supplements prior to experiencing 36 hours of sleep deprivation did better on a test of executive functioning than nonsupplemented individuals (McMorris et al., 2006). Creatine supplements have additionally been shown to enhance working memory in vegetarians, who typically have lower levels of creatine than omnivores (Rae et al., 2003), and to improve performance on tests of verbal and spatial memory in elderly individuals (McMorris et al., 2007).
There is growing evidence that creatine may be of value in the treatment of a number of neurological conditions, including congenital creatine deficiency syndromes, age-related cognitive decline (e.g., Alzheimer’s disease), and neurodegenerative diseases (e.g., Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis), all of which are linked to dysfunctional energy metabolism (Andres et al., 2008; Gualano et al., 2010). Creatine supplementation is also beginning to attract attention as a complementary strategy in the treatment of psychiatric disorders (e.g., depression, posttraumatic stress disorder, and schizophrenia) (Allen et al., 2010; Amital et al., 2006b; Roitman et al., 2007).
As described in Chapter 3, damage following traumatic brain injury (TBI) can be categorized as primary, secondary, and long-term. Although understanding of the mechanisms underlying secondary injury is yet in its early stage, data indicate that impairments of mitochondrial function play a role in mediating the delayed consequences of TBI (Andres et al., 2008; Scheff and Dhillon, 2004; Sullivan et al., 2000; Zhu et al., 2004). It has been hypothesized that creatine’s neuroprotective effects following TBI may involve creatine-induced maintenance of mitochondrial bioenergetics (Sullivan et al., 2000). Supporting this hypothesis is the finding by Sullivan and colleagues (2000) that rats fed a diet containing one percent creatine for four weeks displayed significantly higher mitochondrial membrane potentials and maintained levels of ATP better than nonsupplemented rats following controlled cortical contusion. Other indications of improved mitochondrial function in creatine-treated rats included decreased levels of reactive oxidative intermediaries and intramitochondrial calcium.
Brain levels of both lactate and free fatty acids increase following focal brain injury. These increases are believed to be a consequence of secondary brain damage resulting from the accumulation of excitotoxic levels of the neurotransmitter glutamate. Scheff and Dhillon