Melatonin madness

Melatonin madness is everywhere! The media attention that melatonin has received recently is truly remarkable and has elevated the hormone to cult status. Is all this excitement really justified, or is it just hype? What does melatonin actually do? Does it signal through specific receptors like other hormones? What is its true therapeutic potential? This minireview addresses these questions and highlights recent discoveries that increase our understanding of the cellular and molecular actions of this hormone. Melatonin is the principal hormone of the vertebrate pineal gland. Pineal melatonin production exhibits astriking circadian rhythm that is reflected in circulating melatonin levels. In mammals, the melatonin rhythm is generated by a master circadian clock in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN is synchronized (entrained) to the 24 hr day by the daily light-dark cycle, with light signaling through adirect retinal pathwayto SCN. The SCN clock sends circadian signals over a multisynaptic neural pathway to the pineal gland, driving rhythmic melatonin production. Within the pineal gland, melatonin is synthesized from serotonin (5-hydroxytryptamine [5-HT]). The rate-limiting step in melatonin production is the N-acetylation of 5-HT by arylalkylamine N-acetyltransferase (AANAT), an enzyme whose cDNA has been recently cloned (Coon et al., 1995). The AA-NAT rhythm is under SCN control, with the resulting melatonin rhythm distinguished by high levels at night in all vertebrates. The “Melatonin Miracle” Is a Mirage A centerpiece of the so-called melatonin miracle sensationalized in a recent pop science book is the claim that the hormone can reverse aging (Pierpaoli and Regelson, 1995). This assertion is scientifically unfounded and is based on the results of a seriously flawed study performed in mice (Pierpaoli and Regelson, 1994). All the murine strains used in that study (BALB/c, C57BL/6, and NZB) have a well-described genetic defect in pineal melatonin biosynthesis and cannot make melatonin (Goto et al., 1994, and references therein). Thus, any assertion that youthful pineal glands transplanted into old mice keep old mice from aging owing to restoration of “youthful” melatonin levels is absurd. When these melatonin-deficient strains of mice were treated with pharmacological doses of melatonin, there was a 20% increase in life span in female NZB and BALBlc mice, but not in female C57BL/6 mice. However, these authors showed in another study (that is generally overlooked) that when comparable amounts of melatonin are given to a mouse strain (C3H/ He) that makes melatonin, the treatment actually shortened survival by inducing reproductive tract tumors (referenced by Pierpaoli and Regelson, 1994). Thus, there is no evidence that melatonin administered to melatoninproducing mice can increase longevity. The evidence that melatonin can increase longevity in mice in general is inconsistent The suggestion that melatonin may increase longevity is humans is based purely on speculation. The antioxidant effect of melatonin has also been embellished, leading to claims that melatonin is a wonder drug useful for treating everything from AIDS to Alzheimer’s disease (Reiter and Robinson, 1995). Melatonin does act as an intracellular scavenger of hydroxyl and peroxyl free radicals when administered at pharmacological doses both in vivo and in vitro (reviewed by Reiter, 1995). Although the antioxidant potential of melatonin may have some therapeutic applications (although clearly not as many as claimed!), these antioxidant effects require melatonin concentrations about 106-fold greater than the physiological melatonin concentration (which is <l nM). Thus, the antioxidant effects of melatonin, being pharmacological, would not be expected to be mediated through physiologically relevant high affinity receptors. To no great surprise, advocates of melatonin’s antioxidant abilities have embraced with open arms the unsubstantiated claims that melatonin may signal through low affinity nuclear receptors of the retinoid Z receptor family (Becker-Andre et al., 1994; Wiesenberg et al., 1995). Melatonin Has Specific Neurobiological Effects Melatonin does have several bona fide biological effects that are mediated through high affinity receptors (Figure 1). The most well-documented physiological role of melatonin is its regulation of seasonal responses to changes