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(The FASEB Journal. 2000;14:1464-1469.)
© 2000 FASEB

Putative role of neuronal 5-lipoxygenase in an aging brain

HARI MANEV1, TOLGA UZ, KIMINOBU SUGAYA and TINGYU QU

The Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois 60612, USA

1Correspondence: The Psychiatric Institute, University of Illinois at Chicago, 1601 West Taylor St., MC 912, Chicago, Illinois 60612, USA. E-mail: HManev{at}psych.uic.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 NEURONAL 5-LOX
 ENZYMATIC AND NONENZYMATIC...
 5-LOX GENE EXPRESSION: EFFECT...
 5-LOX INHIBITORS FOR AGING...
 REFERENCES
 
Aging is associated with increased incidence and/or severity of neurodegenerative pathologies. Oxygen-mediated events are being considered as possible mechanisms responsible for the increasing neuronal vulnerability. Lipoxygenases are enzymes that, as cyclooxygenases (COX), can insert oxygen into the molecule of arachidonic acid and thereby synthesize inflammatory eicosanoids: leukotrienes [due to 5-lipoxygenase (5-LOX) activity] and prostaglandins (via COX activity). It appears that 5-LOX is expressed in central nervous system neurons and may participate in neurodegeneration. 5-LOX-triggered cell death may be initiated by the enzymatic activity of 5-LOX but could also occur via the nonenzymatic actions of the 5-LOX protein; new data point to the possibility that 5-LOX protein exerts actions such as interaction with tyrosine kinase receptors, cytoskeletal proteins, and the nucleus. The expression of neuronal 5-LOX is susceptible to hormonal regulation, presumably due to the presence of hormone-responsive elements in the structure of the 5-LOX gene promoter. The expression of the 5-LOX gene and the activity of the 5-LOX pathway are increased in elderly subjects. One possible mechanism of such 5-LOX up-regulation implies the contribution of aging-associated hormonal changes: relative melatonin deficiency and/or hyperglucocorticoidemia. Thus, the 5-LOX pathway could become a promising target of neuroprotective therapies for the aging brain.—Manev, H., Uz, T., Sugaya, K., Qu, T. Putative role of neuronal 5-lipoxygenase in an aging brain.


Key Words: 5-LOX • aged-associated CNS alterations • neuronal degeneration • cyclooxygenase • COX


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
NEURONAL 5-LOX
 ENZYMATIC AND NONENZYMATIC...
 5-LOX GENE EXPRESSION: EFFECT...
 5-LOX INHIBITORS FOR AGING...
 REFERENCES
 
AGING IS ASSOCIATED with an increased vulnerability of central nervous system (CNS) neurons to degeneration and with CNS-related functional deficits. In experimental animals, for example, greater neuronal damage after the initiation of amyloid ß-protein-triggered neurotoxicity (1) or glutamate receptor-mediated excitotoxicity (2 , 3) was observed in old than in young subjects. Functionally, aged rats have also exhibited an impaired ability to sustain long-term potentiation (LTP), a form of synaptic plasticity that has been proposed as a biological substrate for learning and/or memory (4) . Moreover, aged rats exhibit impaired spatial learning in the Morris water maze, and the degree of behavioral impairment has been positively correlated with markers of oxidative stress in the hippocampus (5) . The general contribution of free radicals and oxidative stress to aging was recently reviewed by Harman (6) , and additional mechanisms that may contribute to the aging-associated CNS alterations responsible for increased vulnerability include hormonal influences (particularly those related to stress hormones) (7) and inflammatory pathways (3 , 5) . Here we discuss the influence of aging on the interplay between the inflammatory 5-lipoxygenase (5-LOX; also named 5-LO, 5-LPOx, and ALOX5) and hormonal regulatory mechanisms and the putative contribution of the 5-LOX system to brain vulnerability.


   NEURONAL 5-LOX
TOP
 ABSTRACT
 INTRODUCTION
 NEURONAL 5-LOX
ENZYMATIC AND NONENZYMATIC...
 5-LOX GENE EXPRESSION: EFFECT...
 5-LOX INHIBITORS FOR AGING...
 REFERENCES
 
Neurons of the CNS are rich in arachidonic acid (polyunsaturated fatty acid; 20:4, n-6), which cannot be completely synthesized in the brain but is formed via chain elongation and desaturation from dietary sources, particularly from linoleic acid. Three major types of mammalian lipoxygenases are capable of inserting oxygen into the liberated arachidonic acid: 5-LOX, 12-lipoxygenase (12-LOX), and 15-lipoxygenase (15-LOX). Thus, these enzymes metabolize arachidonic acid (but also other fatty acids) into a number of biologically active metabolites. The primary products of lipoxygenase action are hydroperoxyeicosatetraenoic acids (HPETEs). The primary localization of the lipoxygenases is in leukocytes and lymphocytes (5-LOX), platelets (12-LOX), and leukocytes and airway cells (15-LOX). Nevertheless, they are also expressed in numerous other tissues and cell types. The cloning of lipoxygenases has enabled more detailed studies of their tissue localization and expression. Significant neuronal expression was reported for 5-LOX (8 , 9) and 12-LOX (10 , 11) . 5-LOX and 12-LOX mRNA expression was also observed in the pineal gland. The levels of mRNAs encoding these two lipoxygenases in the pineal gland are affected by the circadian rhythm, but in an opposite manner: pineal 5-LOX mRNA levels were found to be higher during the day than during the night (12) whereas 12-LOX mRNA levels peak during the night (13) . It was proposed that these two enzymes might be involved in regulating the circadian functioning of the pineal gland (13 , 14) .

It has been known for some time that the brain is endowed with the 5-LOX enzymatic system. Formation of the peptide-containing leukotriene LTC4 was first demonstrated in the rat CNS by Lindgren et al. (15) . Studies by Lammers et al. (8) have found that both 5-LOX and 5-LOX-activating protein (FLAP; see below for its role in regulating 5-LOX enzymatic activity) are expressed in neurons in various regions of the brain, with the most prominent expression in the hippocampus and the cerebellum. Recent interest in the involvement of inflammatory mechanisms, such as those involving the eicosanoids, in the pathobiology of neurodegeneration has also attracted attention to the putative role of the 5-LOX pathway. One possibility is that an overexpressed/overactive 5-LOX pathway may lead to neurodegeneration by causing lipid peroxidation. For example, it was found in a human neuronal cell line that the gp120 protein of the HIV virus stimulated 5-LOX expression and caused lipid peroxidation and cell death, which was prevented by a 5-LOX inhibitor, caffeic acid (16) . Increased susceptibility to excitotoxic brain injury was found in old rats compared with young ones; old rats also expressed more neuronal 5-LOX than did young rats, and protection against excitotoxicity was obtained with caffeic acid (3) . Mobilization and activation of neuronal 5-LOX was also observed in the response of the brain to ischemia (9) . In those experiments no leukotriene increase was observed during ischemia; reperfusion was required for 5-LOX activation and leukotriene synthesis in an ischemic brain. Protection from hypoxic injury in brain slices was obtained with leukotriene inhibition (17) . Studies in dissociated brain cells have demonstrated that stimulation of the 5-LOX pathway can be triggered by {alpha}-thrombin, which points to a putative mechanism of neuronal 5-LOX activation during blood–brain cell contact, e.g., in stroke (18) . Seizures have also been shown to be capable of causing increased activity of the 5-LOX pathway. In gerbils, seizures induced by kainate (an agonist of ionotropic receptors for the excitatory neurotransmitter glutamate) were accompanied by time-dependent leukotriene formation, which was reduced by an inhibitor of 5-LOX (19) . Similarly, stimulation of glutamate receptors in hippocampal slices led to injury that was reduced by leukotriene inhibition (17) . A combined lipoxygenase/cyclooxygenase inhibitor, BW755C, reduced the severity of seizures and protected significantly from the brain damage induced in rats by systemic administration of 10 mg/kg kainate (20) . On the other hand, such a treatment of rats resulted in an up-regulation of 5-LOX mRNA in the hippocampus and in the redistribution of neuronal 5-LOX-like immunoreactivity (21) . Collectively, these data indicate that 5-LOX may participate in neurodegeneration and that neuroprotection could be obtained by inhibiting this pathway in the brain.

The physiological role of neuronal 5-LOX is not clear. Recently, it was proposed that as opposed to aging, where 5-LOX may play a role, this pathway might be essential in neuronal development (22) . Expression of 5-LOX is greater in developing than in mature neurons in culture (23) , and an inhibition of 5-LOX resulted in cell death in developing but not in mature neurons (22) . Similarly, an inborn error in leukotriene metabolism has recently been found that results in a fatal developmental and neurological syndrome (24) . 5-LOX has also been considered in conjunction with its influence on neuronal somatostatin-mediated signaling (8) , on opioid receptors (25) , and possibly in the regulation of invertebrate light-sensitive channels (26) . Although these and other functional implications of the 5-LOX pathway usually assume that the leukotrienes that are synthesized by activation of 5-LOX are responsible for the biological effects of 5-LOX, it should be stressed that the nonenzymatic action of 5-LOX protein might also be functionally relevant for the CNS (Fig. 1 ).



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  		Figure 1. Putative enzymatic and nonenzymatic actions of 5-LOX protein. In resting cells, 5-LOX appears to be predominantly a cytosolic protein that, depending on the state of its phosphorylation, is capable of binding 5-LOX-activating protein (FLAP) (1), translocating into the nucleus (2), binding receptor-bound protein 2 (Grb2) (3), or binding to coactosin-like protein, which appears to be linked to the cytoskeleton (4) (see text for details and references). 1: Interaction of 5-LOX and FLAP enables the enzymatic activity of 5-LOX that catalyzes the insertion of oxygen into free arachidonic acid (AA) and initiates the formation of leukotrienes (LT). The arachidonic acid that participates in LT formation presumably originates in the nuclear membrane, from which it is released by an action of cytosolic phospholipase A2 (cPLA2) (29) . Leukotrienes could affect the cell in which they are produced (e.g., by affecting gene transcription and/or by interacting with membrane-associated LT receptors) or they could leave the cell and affect neighboring cells (neurons?; glia?) via metabotropic G-protein-coupled LT receptors. 2: The functional significance of nuclear 5-LOX import that is not associated with LT synthesis is not clear, as yet (a role in modifying gene transcription?). 3: The intracellular signaling system of tyrosine kinase (TRK) receptors for growth factors include the Ras-mitogen-activated protein kinase (MAPK) cascade, which regulates gene transcription (61) . Involved in this signaling system are the adaptor protein Shc and the Grb2 protein; the latter, with its two SH3 domains, interacts with the protein named ‘son of sevenless’ (Sos). The affinity of 5-LOX for the SH3 domains (32) might enable the 5-LOX protein to influence the signaling in this intracellular pathway. 4: The coactosin-like proteins play a role in capping of the cytoskeletal proteins (e.g., actin) (62) . The affinity of 5-LOX to bind a coactosin-like protein (33) might enable it to participate in cytoskeleton remodeling.


   ENZYMATIC AND NONENZYMATIC ACTIONS OF 5-LOX PROTEIN
TOP
 ABSTRACT
 INTRODUCTION
 NEURONAL 5-LOX
 ENZYMATIC AND NONENZYMATIC...
5-LOX GENE EXPRESSION: EFFECT...
 5-LOX INHIBITORS FOR AGING...
 REFERENCES
 
Classically, 5-LOX protein is of interest because of its enzymatic action, i.e., its capability to catalyze the first part of the two-step lipoxygenation of arachidonic acid in the synthesis of the leukotriene LTA4. This first step is the incorporation of oxygen at C-5 of arachidonic acid, which leads to the formation of 5-HPETE, which is further converted to LTA4. Subsequently, LTA4 is enzymatically converted into other leukotrienes (LTB4, LTC4, LTD4, and LTE4). Leukotrienes are biologically active molecules that may convey messages by interacting with specific membrane G-protein-coupled leukotriene receptors (27) and can probably regulate transcription by binding an intranuclear orphan receptor (28) (Fig. 1) .

It is believed that for its full enzymatic activity 5-LOX, requires FLAP, a membrane-bound protein. Initially, the localization of FLAP was believed to be at the outer cell membrane, whereas more recent data indicate that FLAP is associated with the nuclear membrane. Thus, arachidonic acid released from the nuclear membrane rather than the outer cell membrane may be the primary substrate for leukotriene synthesis (29) (Fig. 1) . Moreover, recent investigations of how FLAP activates 5-LOX propose that 5-LOX does not actually bind FLAP, but rather that FLAP binds arachidonic acid and presents it to 5-LOX in such a manner that 5-LOX becomes fully enzymatically active (29) . Some relatively selective 5-LOX inhibitors have been designed to interfere with the interaction of 5-LOX with FLAP (for review, see ref 30 ).

Complementary to the classical view of 5-LOX as an enzyme, more recent evidence suggests that 5-LOX protein may have an additional regulatory, but nonenzymatic, function. In resting cells, 5-LOX appears to be predominantly a cytosolic protein that, depending on the state of its phosphorylation, is capable of binding FLAP or proteins other than FLAP (31) . It was first described by Lepley and Fitzpatrick (32) that 5-LOX contains an Src homology 3 (SH3) binding motif, which enables the interaction of the 5-LOX protein with growth factor (i.e., tyrosine kinase) receptor-bound protein 2 (Grb2) and with cytoskeletal proteins (31 , 32) . Additional evidence has since been provided that clearly indicates the capability of 5-LOX to bind cellular proteins—in particular, coactosin-like protein, which appears also to be linked to the cytoskeleton (33) . A possible interaction of 5-LOX and the nuclear factor NF-{kappa}B complex formation appears to indicate the possibility that 5-LOX protein might influence the process of transcription (34) . Also of interest is the observation that 5-LOX is capable of entering into the nucleus (29 , 35) . This capability of the 5-LOX protein appears to be determined by an NH2-terminal 5-LOX fragment of 80 residues (35) . Although interesting, the functional implications of the nonenzymatic actions of 5-LOX protein in neurons have not yet been investigated. It is possible, however, that the nonenzymatic role of 5-LOX is unrelated to its participation in inflammatory processes.


   5-LOX GENE EXPRESSION: EFFECT OF AGING AND HORMONES
TOP
 ABSTRACT
 INTRODUCTION
 NEURONAL 5-LOX
 ENZYMATIC AND NONENZYMATIC...
 5-LOX GENE EXPRESSION: EFFECT...
5-LOX INHIBITORS FOR AGING...
 REFERENCES
 
In addition to the regulation of 5-LOX activity by intracellular calcium and ATP levels, the expression of the 5-LOX gene is also subject to complex regulatory mechanisms (36) . Most knowledge about 5-LOX expression has been derived from studies in myeloid cells and is in line with the prominent role of the 5-LOX pathway in immune reactions. However, 5-LOX expression in other tissues, e.g., blood vessels (37) or brain (3) , also appears to be regulated, especially during the organism’s aging. An aging-associated increase in the expression of 5-LOX protein was found to be associated with an increased production of leukotrienes in blood vessels (37) . In cattle alveolar macrophages, an age-dependent increase in steady-state expression of 5-LOX protein was also found to be correlated with the age-related enhancement of 5-LOX metabolic capacity (38) . Recently, a similar age-dependent increase in 5-LOX metabolic capacity was observed in rat alveolar macrophages (39) . The content of 5-LOX mRNA in the brain was also found to be greater in old (24 months) than in young (2 months) rats (3) .

One possibility is that the aging-associated changes in the endocrine system that lead to numerous hormonal alterations in elderly subjects are the underlying mechanisms of altered neuronal 5-LOX gene expression during aging. Namely, the 5-LOX gene promoter appears to contain hormone response elements, which indicates its strong susceptibility to hormonal regulation (40) . At least two hormones, glucocorticoids and melatonin, whose secretion is altered during aging, are the probable regulators of 5-LOX gene expression. Glucocorticoid levels (cortisol in humans, corticosterone in rats) are increased during aging, and this increase has been correlated with brain pathology (41 , 42) . Melatonin synthesis/secretion, on the other hand, decreases with aging (43 , 44) , and melatonin deficiency has been associated with increased brain vulnerability (45 , 46) . Although there are no data pointing to a direct action of glucocorticoid receptors on the 5-LOX gene promoter, the possibility of such an interaction can be assumed based on the presence of the ‘AGAACA’ sequence in the response element of this promoter (bp -1804 to -1809) (40) , a sequence indicative of the partial glucocorticoid response element (47 , 48) . In line with this is evidence that glucocorticoids stimulate the expression of 5-LOX mRNA in vitro (49) and in vivo (50) . In the brain of rats treated for 10 days with either corticosterone or with dexamethasone, the glucocorticoid-induced increase of 5-LOX mRNA was accompanied with an increase in 5-LOX protein content (50) .

Melatonin, however, appears to exert an inhibitory action on 5-LOX expression. The content of hippocampal 5-LOX mRNA in melatonin-deficient, pinealectomized rats was found to be significantly lower than that in the hippocampi of corresponding controls (51) . The mechanism of melatonin-mediated regulation of 5-LOX gene expression may involve the interaction of this hormone with a subtype of a retinoic acid-like family of nuclear receptors (52 , 53) . It was shown that by interacting with these receptors, melatonin is capable of suppressing 5-LOX expression (52) . Hence, the stimulatory action of glucocorticoids and the inhibitory action of melatonin on 5-LOX gene expression in the brain are consistent with the effects of aging on both the levels of these hormones (increased glucocorticoids and decreased melatonin in old subjects) and on the brain content of 5-LOX mRNA (increased in old rats; 3 ).

Additional regulatory factors that could play a role in the regulation of 5-LOX gene expression include early-growth response factor-1, cAMP-response element binding-protein binding protein (CBP), and the CBP-related protein p300 (54) . In addition, there are naturally occurring mutations in the 5-LOX gene promoter that may also influence the rate of 5-LOX expression (55) . Whether these mechanisms are operative in regulating neuronal 5-LOX expression and are affected by aging has not yet been investigated.


   5-LOX INHIBITORS FOR AGING-ASSOCIATED BRAIN PATHOLOGY
TOP
 ABSTRACT
 INTRODUCTION
 NEURONAL 5-LOX
 ENZYMATIC AND NONENZYMATIC...
 5-LOX GENE EXPRESSION: EFFECT...
 5-LOX INHIBITORS FOR AGING...
REFERENCES
 
Based on the above-described evidence indicating a role for 5-LOX in neurodegeneration, it is becoming apparent that drugs capable of suppressing this inflammatory pathway might be useful in treating aging-associated neurodegenerative diseases such as Alzheimer’s. Recent clinical studies point to the beneficial effects of antiinflammatory treatments in Alzheimer’s patients (56 , 57) . The drugs considered in such studies belong predominantly to a family of nonselective nonsteroid antiinflammatory drugs (NSAIDs). More recently, attention has been directed toward the development of selective cyclooxygenase-2 (COX-2) inhibitors (58) . On the other hand, no clinical studies have yet been reported about the use of specific 5-LOX inhibitors in Alzheimer’s patients or in any other neurodegenerative disease. Zileuton, currently the only clinically available selective 5-LOX inhibitor, is being used to treat asthma (59) . Whether the blood–brain permeability of this drug is sufficient to allow for its trial in neurodegenerative diseases is not clear. If so, a pilot study of zileuton in Alzheimer’s patients would be indicated. Moreover, based on the evidence that 5-LOX expression differs between young and old subjects, it is possible that the efficacy of selective 5-LOX inhibitors in reducing 5-LOX-mediated pathologies will be greater in elderly than in young subjects; namely, a similar concept was recently indicated by a study that addressed the role of the 5-LOX promoter genotype in the response of asthma patients to treatment with 5-LOX inhibitors (60) . Since the presence of a naturally occurring family of DNA sequence variants in the 5-LOX gene promoter diminished promoter-reporter activity in vitro (55) , Drazen et al. (60) suggested that patients with such sequence variants may have diminished gene transcription and, therefore, a diminished clinical response to treatment with 5-LOX inhibitors. We propose that the opposite could be the case in elderly subjects: due to increased neuronal 5-LOX expression in aging, the elderly could respond better than the young to treatment with selective 5-LOX inhibitors. Future studies are needed to fully evaluate the role of the 5-LOX pathway in the pathobiology and treatment of aging-associated neurodegenerative diseases.


   ACKNOWLEDGMENTS
 
This work was supported in part by the National Institute on Aging grant RO1-AG15347 (H.M.) and by the University of Illinois at Chicago Campus Research Board Award, CRB F98 (H.M.). We thank Ms. Karin Riggs for help in preparing the figure.

Received for publication August 18, 1999. Revision received November 22, 1999.
   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 NEURONAL 5-LOX
 ENZYMATIC AND NONENZYMATIC...
 5-LOX GENE EXPRESSION: EFFECT...
 5-LOX INHIBITORS FOR AGING...
 REFERENCES
 

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