Pharmacological Strategies to Improve Mitochondrial Function in Aging or AD
While the concept of Aß-induced mitochondrial dysfunction as a major functionally relevant pathomechanism in AD has received substantial support over the last decade, improving mitochondrial function as a target for new drug development has rather not, as most interest has been directed to drugs leading to reduced Aß load (Lemere et al., 2004). However, as several compounds out of those disease-modifying drug classes have recently failed to show clinical effectiveness in AD trials (Gura, 2008), a report about substantial therapeutic effects of dimebon in a 1-year clinical trial (Doody et al., 2008) received large attention. Quite interestingly, although originally used as an antihistaminic drug, dimebon was later characterized as a mitochondrial stabilizer with rather similar properties as reported for piracetam in the present communication (Bachurin et al., 2003; Bernales et al., 2008). The concept of using mitochondrial protection as treatment strategy for dementia has recently been further supported by a preliminary report about again substantial clinical improvement in AD patients treated with methylene blue (Gura, 2008). Importantly, this drug not only has been shown to enhance cognitive functions in several animal studies associated with elevated oxygen consumption, but also seems to enhance mitochondrial function by activating complex I and IV activities at the cellular level (Callaway et al., 2002; Callaway et al., 2004; Atamna et al., 2008).
The close association and common basis of oxidative stress and mitochondrial dysfunction in brain aging and age-related neurodegenerative disorders like AD (see the previous chapters) explains that several antioxidants have a long history as possible treatments for AD and even have been and are used in this context. Initially mainly Vitamin E or Vitamin C or the combination of both was investigated (Bastianetto and Quirion, 2004; Farlow et al., 2008; Lee et al., 2009). While both at high concentrations definitively show antioxidant properties in vitro and in vivo, their therapeutical benefit to improve or even prevent cognitive impairment in the elderly is at present seen rather critically.
Another important class of naturally accruing antioxidant are flavonoids or other polyphenols, which also are fairly good antioxidants which reduced oxidative stress in vitro and in vivo. Flavonoids also improve mitochondrial dysfunction and seem to have therapeutical benefit for long-term treatment of age-related cognitive impairment animals and men (Schmitt-Schillig et al., 2005; Schaffer et al., 2006). The significant reduction of the risk in getting AD by Mediterranean diet is very likely explained to an impotent part by the high daily intake of flavonoids (Scarmeas et al., 2006, 2007). In general, even if the effectiveness of those natural occurring antioxidants to protect against AD seems to be limited, they seem to be the major players of diet in reducing oxidative stress and acting as a second however considerably weaker defense system.
Another case of a herbal drug is the standardized Ginkgo biloba extract (EGb 761), which has been used for many years as a prescription or OTC drug in many countries to treat aging-related cognitive disorders including AD (Christen and Maixent, 2002). EGb 761 contains 24% of flavonoids and 6% of terpenens (Sastre et al., 2002; Abdel-Kader et al., 2007). While the flavonoid fraction seems to be mainly responsible for the free radical scavenging properties, several terpene lactones (Ginkgolides, Bilobalide) show substantial mitochondria-protecting properties (Abdel-Kader et al., 2007).