Prostaglandins

The main problem with any study of prostaglandins (PGs) is that although brain concentrations can exceed 0.1 ^g/g, they appear to be formed on demand, rather than preformed and stored and they have very short half-lives (seconds). Also specific effective antagonists remain to be developed and PGs are widely and evenly distributed, unlike many NTs. Thus any analysis of their central effects rests heavily on either studying PG release, or their effects when applied directly (icv injection). Certainly the brain has the enzymatic ability to synthesise both prostaglandins (cycloxygenase) and leukotrienes (lypoxygenase) from arachidonic acid (AA) (see Fig. 13.8) and a number of central functions have been proposed for them (see Piomelli 1994).

When injected into the brain (often in rather large concentrations) PGE2 but not PGF2 is a depressant and causes sedation and catatonia. PGEs can be found in superfusates of cat cortex and their concentration is increased by direct electrical stimulation as well as by afferent nerve activation. In fact, when given intraventricularly PGE1 and PGE2 antagonise convulsions induced by leptazol and electroshock but whether PGs have any

Figure 13.8 Products of arachidonic acid metabolism. The action of cyclooxygenase produces the cyclic endoperoxides PGG2 and PGH2 and the prostaglandins PGE2, PGF2a and PGD2: lypoxygenase activity gives rise to leukotrienes. The classification D,E,F,G,H depends on the number and position of the hydroxy groups. The subscript (2) describes the number of double bonds. It is the (2) derivatives that appear to be active pharmacologically. Bonds which lie in front of the plane of the cyclopentane ring. = Bonds which lie behind the plane of the ring.

Figure 13.8 Products of arachidonic acid metabolism. The action of cyclooxygenase produces the cyclic endoperoxides PGG2 and PGH2 and the prostaglandins PGE2, PGF2a and PGD2: lypoxygenase activity gives rise to leukotrienes. The classification D,E,F,G,H depends on the number and position of the hydroxy groups. The subscript (2) describes the number of double bonds. It is the (2) derivatives that appear to be active pharmacologically. Bonds which lie in front of the plane of the cyclopentane ring. = Bonds which lie behind the plane of the ring.

role in initiating or controlling convulsive activity is uncertain. The levels of a number of PGs, especially PGD2 and PGE2, are reported to be significantly lowered in spontaneously convulsing gerbils and in these animals the levels of brain lypoxygenase derivatives have also been found to increase after the onset of seizures (Simmet, Seregia and Hertting 1987), although such changes could result from, rather than cause, the convulsions.

PGD2 and PGE2 receptors are concentrated in the preoptic region of the basal forebrain which is known to be imporant in sleep production and when injected into that area PGD2 does induce sleep. In fact PGD2 synthesis increases in rat cortex in the light period of a dark/light cycle when rats normally sleep and when infused into the third ventricle it induces a seemingly natural sleep at very low (—^M) concentrations.

One area of particular interest, in view of the anti-pyretic effects of cyclo-oxygenase inhibitors like aspirin, is the possible role of PGs in the control of body temperature. Thus icv injections of PGE1 and PGE2 elevate body temperature and PGE levels increase in CSF following pyrogen-induced fever. Unfortunately this release does not occur near the anterior hypothalamus, which is considered to control body temperature, and iontophoretically applied PGE2 does not affect the firing of hypothalamic neurons. Also lesions of the anterior hypothalamus abolish PGE- but not pyrogen-induced fever. The situation remains to be resolved (see Wolfe 1982).

Interest in the PGs has recently reverted to their precursor arachidonic acid (AA), which seems to be able to act intracellulary as a second messenger, and also extra-cellularly. In this latter mode it may play a part in LTP. It is known that AA produces a long-lasting enhancement of synaptic transmission in the hippocampus that resembles LTP and in fact activation of NMDA receptors leads to the release of AA by phospholipase A2 (see Dumuis et al. 1988) and inhibition of this enzyme prevents the induction of LTP. AA has also been shown to block the uptake of glutamate (see Williams and Bliss 1989) which would potentiate its effects on NMDA receptors. This would not only prolong LTP but also cause neurotoxicity.

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