Nitric Oxide

Super Memory Formula

Natural Ways to Treat Dementia

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Kiyofumi Yamada and Toshitaka Nabeshima Abstract

Among three isoforms of nitric oxide (NO) synthase, both neuronal and endothelial NO synthases may play an important role in learning and memory. NO production in the brain increases, in an activity-dependent manner, following an increase in intracellular Ca2+ levels. Electrophysiological studies revealed that the NO/cGMP pathway plays an important role as an intercellular messenger in the long-term potentiation and long-term depression, which is considered the cellular basis of learning and memory. Behavioral studies further support the role of NO in learning and memory. Collectively, the evidence suggests that NO plays a crucial role in certain forms of learning and memory formation. Furthermore, we believe that modulation of the NO/cGMP signaling pathway is a novel therapeutic strategy for at least some patients with cognitive impairments such as senile dementia.

Introduction

The cellular basis of learning and memory is an alteration in the effectiveness of synapses, which is called synaptic plasticity. Several studies have suggested a relationship between synaptic plasticity and memory.16 Extensive study of the molecular mechanisms of long-term changes in electrophysiological responses at synapses, such as long-term potentiation (LTP)9 and long-term depression (LTD),40 has led to a better understanding of the cellular basis of learning and memory,90,98 although the existence of a direct relation between LTP and memory has been questioned.53,58

Nitric oxide (NO) production in the brain was first reported by Garthwaite et al in 1988.28 They demonstrated that the excitatory amino acid glutamate evokes the release of an endothelium-derived relaxing factor (EDRF)-like molecule, NO, in cerebellar slices, by activating N-methyl-D-aspartate (NMDA) receptors.28 Subsequent studies have demonstrated that NO acts as an intercellular messenger in the brain and plays a crucial role in synaptic plasticity such as LTP and LTD, as well as learning and memory formation.32

In this chapter, we first give an outline of the regulation of NO synthesis in the brain, and then review electrophysiological and behavioral findings that imply a role for NO in learning and memory. Lastly, we describe the alterations of NO synthesis in the brain induced by learning and memory, and aging.

Regulation of NO Synthesis in the Brain

NO is synthesized from L-arginine by NO synthase (NOS) in a NADPH-dependent reaction. Several isoforms of NOS have been purified and molecularly cloned. Both neuronal NOS (nNOS) and endothelial NOS (eNOS) are calcium/calmodulin-dependent enzymes.13,21 nNOS is constitutively expressed in certain populations of neurons in the CNS. eNOS is also constitutively expressed mainly in endothelial cells59 but also in the CA1 pyramidal cells of the hippocampus.23 In contrast to these two isoforms, inducible NOS (iNOS) is calcium-independent and expressed only after exposure to certain cytokines and/or bacterial endotoxins such as lipopolysaccharide.59'97 It is suggested that NO synthesized by iNOS plays a pathophysiological role in ischemic brain damage and other neuroinflammatory diseases.38'8

Studies both in vitro and in vivo have demonstrated that NO synthesis in neurons is stimulated by Ca2+ influx, which is induced by activation of ionotropic and metabotropic glutamate receptors. NO activates soluble guanylyl cyclase (sGC) which leads to the formation of cGMP13'21'88'89 Although relatively few neurons express NOS in the brain, the NO released could influence surrounding neurons over a wide area because it diffuses rapidly within spatial limits of approximately 0.3-0.4 mm.87

Another potential factor, which may modulate NO synthesis in the brain, is the availability of the precursor L-arginine in the NOS-containing neurons. L-Arginine is present in glial cells in the brain,3 and its release was shown in cerebellar slices in vitro30 and in the thalamus in vivo.24 Systemic treatment with L-arginine, as well as direct infusion into the brain, produces a significant increase in NO synthesis in the brain.74,88 In addition, an increase in extracellular L-arginine and NO metabolite (nitrite and nitrate) levels were observed when the glial function was impaired by treatment with the glial selective metabolic inhibitor fluorocitrate. 6,96 It is proposed that the glial toxin impairs the function of glial cells as a reservoir of L-arginine, leading to leakage of L-arginine from glial cells, which results in an enhancement of NO production by NOS-containing neurons.96 Proposed mechanisms for the modulation of NO synthesis in the brain are illustrated in Figure 1.

Role of NO in LTP and LTD

LTP in the hippocampus refers to the phenomenon whereby a brief, high-frequency electrical stimulation of an excitatory pathway to the hippocampus produces a long-lasting enhancement in the strength of the stimulated synapse.9 Pharmacologic as well as genetic blockade of NMDA receptors prevents the induction of hippocampal LTP without affecting normal synaptic transmission. 73,82 The expression of LTP is thought to involve, in part, a presynaptic increase in transmitter release, implying that postsynaptic neurons release retrograde messengers acting on presynaptic nerve terminals. NO is a potential candidate for such a retrograde messenger.32 NO binds iron in the heme of sGC, altering the conformation to activate the molecule, which leads to formation of cGMP. Presynaptic injection of cGMP produces activity-dependent LTP in cultured hippocampal neurons. Based on experiments using a hippocampal cell culture system, the cellular mechanism of LTP has been proposed as follows: Tetanic stimulation causes Ca2+ influx through postsynaptic NMDA receptors and/or voltage-dependent calcium channels, thereby activating NOS in the postsynaptic neurons. NO then diffuses across the extracellular space to the presynaptic terminal, where it activates sGC and cGMP-dependent protein kinase (PKG) to produce an activity-dependent long-lasting enhancement of transmitter release4,101 (Fig. 1). A recent study, however, revealed that cGMP-dependent protein kinases are not involved in LTP and that NO induces LTP through an alternative cGMP-independent pathway, possibly ADP-ribosylation in mice lacking cGMP-dependent protein kinases.42

Initial pharmacological studies suggested that NO is involved in LTP as a retrograde messenger29,61,75 but there is no consensus on the role of NO in LTP6,51,85 (Table 1). These discrepancies suggest that there are NO-dependent and independent forms of LTP. Alternatively, the results may be partly due to the stimulation pattern used to elicit LTP. High-frequency stimulation to induce LTP is different from neuronal activity under physiological conditions, and thus may lead to NO-independent forms of LTP A recent study showed that the hippocampal LTP in vivo that was induced by a stimulation phase-locked with a theta rhythm, a more physiological stimulation pattern, is completely blocked by NOS inhibitors.34 LTP in the hippocampus has been found to exhibit an early phase that is independent of protein and RNA synthesis (E-LTP) and a late phase that is reduced by inhibitors of those processes (L-LTP). Most studies into the role of NO in LTP have focused on E-LTP, not L-LTP. It has recently been demonstrated that NO contributes to L-LTP via the activation of sGC, PKG and CREB phosphorylation.50

Ltp And Ltd Nmda

Figure 1. Regulation of NO synthesis in the brain and the role of NO in LTP. L-Arginine (L-Arg) is stored in glial cells. NO is synthesized by nNOS and/or eNOS from L-Arg in neurons. In the LTP, tetanic stimulation causes Ca2+ influx through postsynaptic NMDA and/or voltage-dependent calcium channels (VDCCs), thereby activating NOS in postsynaptic neurons. NO then diffuses across the extracellular space to the presynaptic terminal, where it activates sGC and cGMP-dependent protein kinase PKG to produce an activity-dependent long-lasting enhancement of neurotransmitter release.

Figure 1. Regulation of NO synthesis in the brain and the role of NO in LTP. L-Arginine (L-Arg) is stored in glial cells. NO is synthesized by nNOS and/or eNOS from L-Arg in neurons. In the LTP, tetanic stimulation causes Ca2+ influx through postsynaptic NMDA and/or voltage-dependent calcium channels (VDCCs), thereby activating NOS in postsynaptic neurons. NO then diffuses across the extracellular space to the presynaptic terminal, where it activates sGC and cGMP-dependent protein kinase PKG to produce an activity-dependent long-lasting enhancement of neurotransmitter release.

LTP in the hippocampus is normal in mice with a targeted mutation of nNOS or eNOS,62,78 but is eliminated in double mutants for nNOS and eNOS.78 Inhibition of the membrane localization of eNOS results in an inhibition of LTP in the hippocampus.41 It is shown that LTP in the CA1 subfield of the hippocampus of eNOS knockout mice was entirely absent under weak stimulation conditions although strong tetanic stimulation induced a robust LTP which was not blocked by NOS inhibitors.86

LTD in the cerebellum involves a persistent reduction of transmission efficacy at synapses from parallel fibers to Purkinje cells, which occurs when the parallel fibers are activated in conjunction with climbing fibers converging at the same in the cerebel lum is thought to be a cellular basis of motor learning.76 Stimulation of white matter of the cerebellum increases the NO concentration in the molecular layer. A NOS inhibitor NG-monomethyl-L-arginine acetate (L-NMMA) and an NO scavenger hemoglobin inhibit LTD77 (Table 1). LTD cannot be induced in Purkinje neurons of cerebellar slices from young adult nNOS knockout mice.49

The induction of LTP and LTD is not restricted to the hippocampus and cerebellum. Activity-dependent synaptic plasticity is induced in many other areas of the brain (Table 1). For instance, NO-dependent LTP was demonstrated in layer V of the auditory cortex84 and the medial amygdaloid nucleus.1 NMDA-independent, but NO-dependent LTP can be induced in the somatosensory cortex of mice, although it is not induced in eNOS knockout mice.31 High-frequency stimulation of corticostriatal glutamatergic fibers induces LTD in striatal spiny neurons, and the NO/cGMP pathway plays a critical role in the corticostriatal LTD.15

Table 1. Role of NO in

LTP and LTD

LTP/LTD

Effect

Drugs/Mutant Mice

References

LTP in the hippocampus

Inhibition

L-NA, L-NMMA,

61

L-NAME,

75

Hemoglobin,

29

HMA

41

7-NI, TRIM

34,50

Temperature &

L-NA, L-NAME,

85

age-dependent

Hemoglobin

Conditioning-

L-NA

51

dependent

No effect

L-NAME

6

No change

nNOS mutant mouse

62

eNOS mutant mouse

78

Impairment

nNOS/eNOS

78

double mutant mouse

eNOS mutant mouse

86

LTP in the neocortex

Inhibition

L-NAME, L-NMMA

84

Hemoglobin

31

Impairment

eNOS mutant mouse

31

LTD in the cerebellum

Inhibition

L-NMMA,

77

Hemoglobin

Impairment

nNOS mutant mouse

49

LTD in the corticostriatal

Inhibition

L-NAME, 7-NI

15

pathway

Induction

SNAP

15

HMA: hydroxymyristic acid (a myristoylation inhibitor) SNAP: S-nitroso-N-acetylpenicillamine TRIM: 1-(2-trifluoromethylphenyl)imidazole

HMA: hydroxymyristic acid (a myristoylation inhibitor) SNAP: S-nitroso-N-acetylpenicillamine TRIM: 1-(2-trifluoromethylphenyl)imidazole

Role of NO in Memory Processes

As described above, NO plays an important role in LTP and LTD, suggesting that this intercellular messenger participates in some forms of learning and memory. This hypothesis has been tested in a number of studies with various behavioral tasks and NO-related agents (NOS inhibitors, NO donors, L-arginine, GC inhibitors, cGMP analogs, cGMP-dependent phosphodiesterases inhibitors). Some of these studies showed positive results supporting the involvement of NO in memory formation while others reported negative results70,90 (Table 2). Accordingly, it is suggested that NO plays a role in certain forms of learning and memory but not others. Alternatively, nNOS and eNOS may have different roles in learning and memory processes. To test this hypothesis, the effects of specific inhibitors for each NOS isoform have been investigated in various behavioral tasks. Although mice with a targeted mutation of each NOS isoform (nNOS and eNOS knockout mice) are available, reports of behavioral experiments with these mutant mice on learning and memory are limited.27

Spatial Learning and Memory

Many studies have examined the role of NO in spatial learning and memory by using the water maze test,5,11,18,25,36 but the results are not unequivocal. Several investigators have shown that systemic administration of the non-selective NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME) as well as the nNOS-selective inhibitor 7-nitroindazole (7-NI) impairs performance in acquisition trials, in which the escape platform was submerged, although

Table 2. Role of NO

in memory processes

Task

Effect

Drugs/Mutant Mice

References

Water maze

Impairment

L-NAME, 7-NI

18, 25, 36

No effect

L-NAME, L-NA

5, 11

Improvement

eNOS mutant mouse

27

Radial arm maze

Impairment

L-NA, L-NAME, 7-NI

12

L-NMMA

92, 36, 79, 102, 55

3-Pannel runway

Impairment

L-NAME

63

Object recognition

Impairment

L-NAME

20

State-dependent

L-NA

10

Operant conditioning

No effect

L-NAME

43

Y-maze

Impairment

L-NAME, 7-NI

93, 94, 52

14-Unit T-maze

Impairment

7-NI

39, 54

Habituation

Impairment

L-NAME

92

Passive avoidance

Impairment

L-NA, 7-NI, L-NMMA

35, 33, 7, 37, 26, 44

Diphenyleneiodonium

72

chloride

No effect

L-NA, L-NAME

12, 5, 93

Olfactory memory

Impairment

L-NAME

12

No effect

L-NA

14, 66

Enhancement

Sodium nitroprusside,

67

L-Arginine

68

Locomotor adaptation

Impairment

L-NMME, Hemoglobin

99

Eyeblink conditioning

Impairment

L-NAME

18

performance in cued trials, in which the platform was placed above the water, was not affected. These earlier studies suggest that NO plays a role in acquisition of spatial memory.18'25'36

In contrast, Bannerman et al5 have shown that although L-NAME impairs spatial learning in the water maze task with multiple trials per day, it has no effect when only one trial per day is used. Based on these and other results, they have suggested that the impairment of performance caused by L-NAME is not due to any direct effect on the mechanism of spatial learning. Blokland et al11 examined the role of hippocampal NO in spatial learning and reversal learning in the water maze test, because spatial learning is highly dependent on hippocampal function.56 Local injection of NG-nitro-L-arginine (L-NA) into the dorsal hippocampus before a daily training session transiently affected search behavior during the training, but failed to affect performance in the probe trials or reversal learning. Accordingly, it was concluded that hippocampal NO is not critically involved in place learning.11

The role of eNOS in learning and memory was investigated with eNOS knockout mice in the water maze test.27 Unexpectedly, a clear improvement in performance was observed in the acquisition trials, although there was no difference between eNOS knockout mice and wild type mice in the cued trials. Thus, the performance of the mutant mice cannot be attributed solely to differences in sensorimotor capacities. Furthermore, eNOS knockout mice performed better in the probe trials and the reversal learning test. It remains to be determined whether the improvement depends on an increased spatial learning capacity per se or whether eNOS gene disruption induces changes in brain processes related to anxiety or reward which might play an important role in memory.27 Pharmacologic studies with selective eNOS inhibitors will provide additional insight into the role of eNOS in learning and memory.

The role of NO in spatial learning and memory has also been investigated in a radial arm maze.12'36'55'79'92'102 All these studies consistently demonstrated an inhibitory effect of NOS

inhibitors on performance in the acquisition trials, suggesting a crucial role for NO in spatial memory formation. We demonstrated that L-NAME, but not D-NAME, impaired performance in a dose-dependent manner during the acquisition of the radial arm maze task, while it failed to affect performance in those rats that previously achieved the task.92 A non-specific NOS inhibitor, L-NAME inhibited both spatial reference and working memory formation in rats whereas a specific nNOS inhibitor 7-NI impaired specifically spatial reference learning in a reference/working memory task without affecting working memory.102 A working memory deficit in rats following the treatment with L-NAME was also demonstrated in the 3-pannel runway test63 and the object recognition test.20 However, a study using the operant conditioning test showed that inhibition of NOS activity induced by L-NAME does not interfere with the learning or retention of basic operant tasks that involve simple spatial or visual analysis.43

Daily administration of L-arginine increased the choice accuracy, by reducing the number of reference memory errors, in the late phase of training on the radial arm maze, although, during this period, NOS inhibitors had little effect.102 Accordingly, it is possible that NO production in the brain changes depending upon the degree of memory formation, such that the level of production is high in the early phase of training, and then decreases with repeated training (Fig. 2). NOS inhibitors may cause an impairment of spatial learning in the early phase of training during which time NO production levels are high. The inhibitory effects of NOS inhibitors would disappear in the late phase of the training when the level of NO production decreases. Although systemic administration in rats of L-arginine increases NO production in the brain,74,88 the effect may appear only when the level of production in the brain is low. It is likely, therefore, that L-arginine increases choice accuracy by increasing NO production in the late phase, but not the early phase of radial arm maze training.

In addition to the water maze and radial arm maze, several other tasks, including the Y-maze,93,94 a 14-unit T-maze39,52,54 and habituation tests,92 have been utilized to assess the role of NO in spatial memory formation. It was demonstrated in a 14-unit T-maze test that learning impairment induced by the nNOS inhibitor 7-NI can be overcome by systemic administration of the NO donor, molsidomine.54 Furthermore, an impairment of spontaneous alternation behavior in a Y-maze induced by systemic administration of NOS inhibitors such as L-NAME and 7-NI, which was associated with a significant decrease in cGMP contents in the hippocampus, was ameliorated by the intracerebroventricular injection of cGMP analogs. These findings suggest that a NO/cGMP pathway in the hippocampus is responsible for spontaneous alternation behavior in the Y-maze.

Collectively, it appears that NO in the hippocampus may play a crucial role in certain forms of spatial learning but not others. It remains to be determined which NOS isoform is responsible for hippocampus-dependent spatial learning and memory.

Fear Memories

The passive avoidance task is widely used for the study of the mechanism of learning and memory because memory processes involved in the task can be manipulated at different phases, such as acquisition, consolidation/retention and retrieval. Since passive avoidance information is stored for a relatively long period, the memory involved in this task is considered long-term memory. In the chick, memory consolidation and/or retention in the passive avoidance task is impaired by treatment with NOS inhibitors33,35 and enhanced by sodium nitroprusside,71 which spontaneously releases NO. These results imply that NO is involved in long-term memory in the chick. Other groups have also shown in mice and rats that NOS inhibitors, administered immediately before or after the training, produce memory impairment.7,26,37 A recent study showed that NO is involved in retention of the passive avoidance response through the modulation of the forebrain cholinergic system.44 In contrast, other studies have failed to find any effect.5,12,93 Therefore, further study is needed to confirm a possible role for NO in long-term memory involved in the passive avoidance task. One study suggested that the effects of NOS inhibitors on learning and memory are state-dependent, indicating that hippocampal NOS

Inhibitory Avoidance Learning Task

Figure 2. Schematic illustration of the hypothetical changes in NO production during memory formation. NO production in the brain changes depending upon the degree of memory formation, such that the level of production is high in the early phase of training, and then decreases with repeated training. NOS inhibitors cause an impairment of spatial learning in the early phase of training during which time NO production levels are high. The inhibitory effects of NOS inhibitors would disappear in the late phase of the training when NO production has decreased. The effect of L-arginine may appear only when the level of NO production in the brain is low. It is likely, therefore, that L-arginine increases choice accuracy by increasing NO production in the late phase, but not the early phase, of radial arm maze training.

Figure 2. Schematic illustration of the hypothetical changes in NO production during memory formation. NO production in the brain changes depending upon the degree of memory formation, such that the level of production is high in the early phase of training, and then decreases with repeated training. NOS inhibitors cause an impairment of spatial learning in the early phase of training during which time NO production levels are high. The inhibitory effects of NOS inhibitors would disappear in the late phase of the training when NO production has decreased. The effect of L-arginine may appear only when the level of NO production in the brain is low. It is likely, therefore, that L-arginine increases choice accuracy by increasing NO production in the late phase, but not the early phase, of radial arm maze training.

inhibition leads to a change in the internal state of animals and this may affect the manner in which it performs in a cognitive task.10 Another study72 showed that day-old chicks trained on a single-trial passive avoidance task suffered significant memory loss from post-training intracranial administration of a selective inhibitor of eNOS, diphenyleneiodonium chloride, although administration of a selective nNOS or iNOS inhibitor at the same time had no effect on retention. Taken together, it is likely that eNOS plays a role in memory formation in the passive avoidance task, which is at least distinct from any role that may be played by nNOS.72

Olfactory Memory

The olfactory bulb is one of the brain structures involved in olfactory memory in animals. Since this structure possesses much activity of NOS, the role of NO in olfactory memory has been examined. Although one study showed impairment of olfactory memory following a systemic injection of L-NAME,12 others did not observe any significant effect induced by a direct injection of L-NA into the accessory olfactory bulb.14,6 Subsequently, it was shown that intrabulbar infusions of NO donors (sodium nitroprusside) and L-arginine induced formation of a pheromone-specific olfactory memory in the absence of mating.67,68 Collectively, it is likely that NO in the olfactory bulb plays a role in olfactory memory.

Motor Learning

LTD in the cerebellum is considered a cellular basis of motor learning. Since NOS inhibitors impair LTD in the cerebellum, NO is considered to be involved in certain forms of motor learning.40 For instance, NOS inhibitors and hemoglobin, which scavenges NO, abolish adaptive control of locomotion to perturbation, a form of motor learning, in the cat.99 Cerebellar and brainstem structures play a critical role in the acquisition and retention of eyeblink conditioning.80 Since L-NAME impairs acquisition of eyeblink conditioning in the rabbit as does selective lesion of the cerebellar cortex,47 it is suggested that NO is involved in normal function or synaptic plasticity in the cerebellar cortex. Furthermore, it is demonstrated that impairment of conditioned eyeblink response by L-NAME is accompanied by a retardation in the formation of conditioning-related activity in the interpositus nucleus.2

Learning and Memory-Associated Changes in NO Production in the Brain

As described above, accumulating evidence supports the hypothesis that NO plays a role in certain forms of learning and memory. If so, memory formation may be accompanied by an increase in NO production in the brain (Table 3). Papa et al69 have shown that intense NADPH-diaphorase staining, a specific histochemical marker for neurons containing NOS22 in the hippocampus is observed 2 hr, but not immediately, after exposure of rats to spatial novelty. The NOS inhibitor L-NA inhibits NADPH-diaphorase staining and behavioral habituation to spatial novelty.69 In passive avoidance learning, intrahippocampal injection of L-NA immediately after training impairs memory retention, and NOS activity as well as cGMP content in the hippocampus increases immediately after training.7,8 Chen et al19 showed that NOS activity and nitrite levels in the hippocampus and cortex, and also the nitrite level in the cerebellum were significantly elevated one day after rats had learned a water-rewarded spatial alternation task in a Y-maze. Furthermore, immunohistochemistry with nNOS antibodies revealed that spatial learning and memory in the same water-rewarded spatial alternation task increased the number of NO-producing neurons in the dentate gyrus and frontal cortex.100 Regarding olfactory memory formation, a stimulus-specific expression of nNOS mRNA was demonstrated, by using an in situ hybridization technique, in the female mouse accessory olfactory bulb.65

These results demonstrate that the levels of NO, as well as cGMP, increase after memory formation in the brain regions, which are considered to be important for learning and memory. Furthermore, the results provide additional evidence for a role of the NO/cGMP signaling pathway in learning and memory.

Conclusions

In this chapter, we first outlined the regulation of NO synthesis in the brain, and then reviewed electrophysiological and behavioral findings that imply a role for NO in learning and memory formation. Among three NOS isoforms, both nNOS and eNOS may play an important role in learning and memory. In NOS-containing neurons, NO production increases, in an activity-dependent manner, following an increase in intracellular Ca2+ levels. Electrophysiological studies revealed that the NO/cGMP pathway plays an important role as an intercellular messenger in the LTP and LTD, which is considered the cellular basis of learning and memory. Behavioral studies further support the role of NO in learning and memory. Collectively, the evidence suggests that NO plays a crucial role in certain forms of learning and memory formation.

It is important to examine whether compounds that can modulate the NO/cGMP signaling pathway have therapeutic potential for the treatment of patients with cognitive

Table 3. Learning and memory-associated changes in NO production in the brain

Task

Marker

Changes

Brain Region

References

Habituation to

NADPH-diaphorase

Increase

Hippocampus

69

spatial novelty

staining

Passive avoidance

NOS activity

Increase

Hippocampus

7

cGMP

Increase

Hippocampus

8

Y-maze

NOS activity

Increase

Hippocampus/

19

nitrite level

Increase

cortex

nNOS

Increase

Gentate gyrus/

100

immunochemistry

Frontal cortex

Olfactory memory

nNOS mRNA

Increase

Accessory

65

olfactory bulb

impairments such as aging-associated memory impairment. Some investigators suggested a decrease in NO synthesis in aged rat brain1 ,60,83,91,95 whereas others suggested increased synthesis.45,48 We believe that modulation of the NO/cGMP signaling pathway is a novel therapeutic strategy for at least some patients with cognitive impairments. Of note, Ohtsuka and Nakaya64 reported an improving effect of oral administration of L-arginine on senile dementia. Other potential candidates include NO donors and inhibitors of cGMP-dependent phosphodiesterase.

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