Fig.1 : picture of  human pineal gland.
(Click on image for larger version.)


                             At first sight, the structure of the mammalian pineal is not very exciting. It lies at the exact centre of the brain behind the eyes as shown in Fig.1 above and consists of only two major cell types, pinealocytes and immature astrocytes. Occasionally, the pinealocytes are arranged in follicles surrounding narrow or wide spaces. The gland is richly innervated by postganglionic sympathetic nerve fibres, most of which are found in the perivascular spaces of capillaries. In addition, pinealopetal fibres of central origin are present (Vollrath 1981). Observed under the light microscope the pineal specific cells, the pinealocytes, lack prominent and differential staining properties. Special staining reagents such as silver impregnation are necessary to demonstrate their complete outlines. Then it becomes apparent that pinealocytes are nerve cell like, consisting of a perikaryon and an unknown number of cytoplasmic processes. The large, pale nucleus with its prominent nucleolus is also reminiscent of a large ganglion cell.  As cytoplasmic basophilia is virtually non existent, there is no satisfactory explanation for the high metabolic activity of pinealocyte nuclei.
                            At the ultra structural level it is quite difficult to relate structure to function. In most mammalian species investigated the pinealocytes contain few granules that can be regarded  as morphological correlated of secretory products, and the circadian behaviour of the few dense core vesicles present does not support the assumption that they contain melatonin. According to Julliard & Collin (1980) dense core vesicles act as storage sites for serotonin. Pinealocyte perikarya house a prominent Golgi apparatus and relatively small amounts of smooth and rough  endoplasmic reticulum. In some species cisternea of the endoplasmic reticulum contain flocculent material  which may represent a form of secretory substances. Highly pleomorphic mitochondria tend to form clusters reminiscent of the ellipsoids of inner segments of photoreceptor cells. That the pinealocytes are responsible for the conversion of serotonin to melatonin has been demonstrated histochemically by showing that it is these cells that contain serotonin (Bertler et al 1963) and melatonin (Freund et al 1977) and not the astrocyte-like interstitial cells.
                            It is generally accepted that  mammalian pinealocytes are phylogenetically derived from pineal photoreceptor cells. In lower vertebrates pineal photoreceptors are similar to retinal cones and show outer and inner segments as well as synapses with afferent pinealofugal nerve fibres. During phylogenesis the outer segments regress as do the pinealofugal nerve fibres, but the synaptic ribbons of the afferent synapses persist. In view of the phylogenetic regression and the current concept that  it is the function of mammalian pinealocytes to synthesize melatonin and to release it into the systemic circulation, both the shape of the pinealocytes and the architecture of the gland are surprising.
                            Human pinealocytes are equipped with long cytoplasmic processes. Comparable processes are present in all mammalian species investigated ultra structurally. When we compare these process bearing cells with the pineal photoreceptor cells of lower vertebrates it is difficult to envisage that mammalian pinealocytes represent regressed photoreceptor cells. Instead it appears that mammalian pinealocytes are highly differentiated cells similar to nerve cells, the process of which receive messages and pass on signals. A puzzling feature is that, although the possible morphological correlates of pineal secretory products are particularly prominent in terminal swellings of pinealocyte processes in many mammalian species, only a few terminals are close to blood vessels. Instead, the perivascular spaces are filled with large bundles of postganglionic sympathetic nerve fibres. In fact, according to  quantitative studies in the rat, 91.1% of the nerve fibres have a perivascular location, the remainder lying between pinealocytes (A.Meyer & L. Vollrath 1985). It is enigmatic that sympathetic nerve fibres predominate in the perivascular spaces since the nervi conari reach the pineal gland independently of blood vessels, as separate nerves.


Sympathetic innervation

                            This type of innervation has been clearly defined both morphologically and functionally. The fibres originate in the superior cervical ganglia (SCG) of the sympathetic trunk, continue in the internal carotid nerve and enter the pineal gland as nervi conari (Zigmaond et al 1981, Bowers et al 1984). Their importance for the regulation fo melatonin synthesis has been demonstrated by biochemical studies after sympathectomy or electrical stimulation of the SCG, the latter leading to an approximately 50 fold increase of serotonin N-acetyltransferase (NAT) activity (Bowers & Zigmond 1980,1982). A study of rat pinealocytes after electrical stimulation of the SCG by Beuss in 1985 reviewed that some pinealocytes did not appear to be influenced by SCG stimulation, a second group responded with enhanced electrical activity and in a third group electrical activity was depressed. In view of the continuing controversy about whether NAT of hydroxyindole O-methyltransferase (HIOMT) is the rate limiting enzyme for melatonin synthesis, and the lack of a clear-cut day / night rhythm of HIOMT, in contrast to NAT, it is relevant to recall that as early as 1972 it was reported that preganglionic electrical stimulation of sympathetic nerves resulted in an increase of pineal NAT activity but a decrease of HIOMT activity.

Central innervation

                            Nerve fibres reach the pineal gland via habenular and posterior commissures   and  now with modern neurobiological techniques available, it becomes apparent that these fibres are of functional importance. Lesion and horseradish-peroxidase studies have revealed that central pinealopetal nerves fibres originate in diverse brain regions including the habenular, paraventricular and suprachiasmatic nuclei as well as the preoptic area, amygdala, olfactory centres, lateral geniculate bodies and the sites of origin of the stria medullaris. The central fibres contain a variety of peptides such as oxytocin, vasopressin, luteinizing hormone-releasing hormone, vasoactive intestinal polypeptide. The fibres are unevenly distributed in the pineal gland, some lying in the periphery and others in the centre. 

                           The mammalian pineal gland evolved from a well differentiated photoreceptive organ in lower vertebrates, a functional third eye . In human, pineal gland is a small pea size structure situated in the middle of the brain. The mean weight of the pineal in a woman is 173 mg which does not differ from the mean weight of 172 mg for a man  . The function of the pineal gland is shown in Fig. 2. Several conditions and compounds arranged in four categories have been listed which are known to influence pineal function. Conditions of stress could affect the pineal either by way of the pineal sympathetic innervation of via the neurohumoral route. On the right or output side, indoleamines and polypeptides are mentioned. These are substances include melatonin which are known to be produced and generally secreted by the pineal.

Fig. 2 : Function of mammalian pineal.
(Click on image for larger version.)

                            The pineal gland does not have the capacity to respond directly to light. Rather, light controls it through a system which includes the lateral eyes, central and peripheral neural structures and neurochemical transduction mechanisms within the gland. All vertebrates appear to synthesize melatonin rhythmically on a 24h basis. Click here to see the amount of melatonin secretion by the human pineal gland during a 24 hour cycle. 

Hormones in the pineal other than melatonin
                    Table 1 : small molecules and peptides in the pineal gland
 Small molecules
Arginine vasotocin
Angiotensin I
Melano-und lipotropins
Iodinated compounds
Reference : A.B.Lerner, J.Neural Trans, Suppl.13,131-133 (1978)
                   The most important role of melatonin is probably the circulation of sleep-wake cycle. In the 1960s, Richard Wurtman did pioneering work on the effects of light and darkness on the secretion of melatonin by the pineal and subsequent research by Wurtman and many others has allowed scientists to trace the neurologic "wiring" of the complex circadian system. The pineal itself is controlled by a paired cluster of nerve cells located just above the optic chiasm in the hypothalamus. These cells are known as the suprachiasmatic nuclei (SCN) and they contain the circadian pacemaker.

                    The effect of light on the melatonin rhythm generating system are properly thought of as effects on the SCN. Although the SCN can function in a cyclic manner autonomously, environmental lighting has strong effects on the changes in pineal N-acetyltransferase ( the enzyme that converts serotonin to melatonin ) activity and melatonin production. The SCN clock is actually composed of two dependent clocks and the degree to which their pineal stimulatory periods overlap is determined by the amount of light. Long nights appear to allow the clocks to drift apart, so that the pineal gland will be stimulated for a longer period than in animal kept in short nights. The effect of exposure to light is also to determinate the neural stimulation of the pineal gland. This results in the decrease in the enzyme N-acetyltransferase and therefore melatonin production. For the biological synthesis of melatonin

                    The amount of melatonin produced is directly linked to the sleep pattern  in mammals including human. The raw material used to made melatonin is the amino acid tryptophan (chemical name).  The tryptophan we consume during the day is converted into serotonin (chemical name), a brain chemical involved with mood. Serotonin in turn is converted into melatonin. The action of melatonin and serotonin  have profound effects on homeostasis, immune surveillance and the maintenance of connective tissue, constructural and muscular components.
                    Other interesting biological properties of melatonin are listed as follow;

Oxidative Stress 

                    The degenerative processes associated with aging is a biologically complex and multifaceted phenomena. A current, but putative theory on aging associates the gradual accumuation of oxidative stress in neural tissue to accelerated neurodegenerative changes and age-related diseases. Oxidative stress is defined as the cellular damage caused by oxygen free radicals. The two types of oxygen free radicals, the superoxide anion and the hydroxyl radical are naturally produced by product of aerobic metabolism, the latter bding more biologically toxic. The reactive nature of free radicals stems from their unpaired valence electron that mediates oxidative toxicity, damaging nucleic acid, membrane lipids, proteins, and carbohydrates. Approximately 5% of celular oxygen is not used in the production of ATP but is reduced to reactive free radicals. An estimated 1011 free radicals/cell/day formed, inducing perhaps up to 105 oxidized DNA residues formed/cell/day. Furthermore, it is suggested that the progression of brain cell aging occurs when the balance between oxidative stress and antioxidative defense tips towards increased free radical production. Neural activity,especially the release of the accumulation of oxidative stress leads to the morphological and physiological destruction of neurons. A gradual deterioration of neurological tissue occurs represented by functional loss, such as slowed reactions, diminished memory, or tremour. This progressive degeneration is the priced the ody pays for utilixing oxygen. Increased free radical generation may also results from the additive exposure to toxins, UV light and stress or from the decrease in the bodies defense sysems to reduce oxidative stress, namely free radical scavengers, antioxidative enzymes, or meal chelating agents.

Melatonin's Protecting Effect

                    Melatonin's protecting role in aging lies in its non-receptro mediated interactions as a potent oxygen radical scavenger. Studies have shown that endogeneous levels of melatonin have oxidative protective effects, with a greater reduction in DNA damage at night, reflecting melatonin's phasic secretion pattern. It scavenges both the superoxide anion and the hydroxyl redical, protecting nuclear DNA, proteins and membrane lipids against free radical damage, as well as stimulating the activity fo glutathione peroxidase, putatively the most important antioxidant in the brain. The indole's lipo and hydrophilicity are properties unique to antioxiidants and allow for  rapid diffusion and accessibility to all subcellular components as well as freely crossing the blood-brain barrier. Other antioxiiidants are confined to particular cellular compartments such as lipid cell membranes for vitamin E and the cytosol for vitiamin C.


                    The pineal gland as an integral constituent of the neuroendocrine system seems to play an important role in modulating the immune response via circadian release of its main neurohormone melatonin and/or some other substances. There is a substantial body of evidence suggesting an antimitotic action of melatonin in mammalian cells in vitro.
                         Possible  mechanisms of interacting between the immune and the pineal gland hormones seems to come full circle with the pathophysiology of the immune disorders. Neuopeptides and neurotransmitters such as endorphins, enkephalins, vasoactive intestinal peptide and the pineal hormones all have significant influence on the immune system, and have been shown to modulate antibody production, natural killer cell activity and response to mitogen. The products of the immune system, on the other hand, has substantial influence on the pineal gland and neuroendocrine system.
                         Similar antineoplastic effect of the pineal gland and its hormone melatonin was observed in fibrosarcoma, in a transplantable form of leukaemia and various form of carcinoma. The enhancement of transplantable tumour growth in pinealectomised animal has been reported long time ago.
                        Modern investigations have revealed that about 50% of pineal tumours in humans are germinomas. Pineal tumours are most common in the Japanese population and occur four to five times more often in males than in females.  In the United States, as many as 40% of tumours in the region of the pineal gland are a mixed historical type. However, studies on the link between the pineal gland and tumour development did not always yield consistent results, though many of the reports pointed to oncostatic action of the pineal. There have also been  several papers reporting that melatonin has no or even stimulatory effects on the growth of some tumours Differences in the results obtained may depend on a number of reasons. In fact, precise comparison of the studies on relationship between the pineal neurohormones and neoplastic growth is very difficult due to the diversity of the experimental approaches i.e. various tumour models used, different methods of measurement of tumour growth (neoplastic cells proliferation, tumour weight, tumour volume), differences in mode and timing of melatonin administration and various photoperiodic environment. In general however, most results have pointed toward an inhibitory effect of melatonin on tumourigenesis. 

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