www.elsevier.com/locate/brainresrev

Brain Research Review

Review

Dual role of nitric oxide in adult neurogenesis

Antonio Cardenas*, Marıa A. Moro, Olivia Hurtado, Juan C. Leza, Ignacio Lizasoain

Instituto de Farmacologıa y Toxicologıa del CSIC, Departamento de Farmacologıa, Facultad de Medicina,

Universidad Complutense de Madrid, Av. Complutense s/n, 28040 Madrid, Spain

Accepted 23 March 2005

Available online 20 April 2005

Abstract

In the last decade, it has been demonstrated that neurogenesis persists in the adult mammalian brain and that it is induced after insults,

where newborn neurons migrate to damaged areas, differentiate and contribute to the recovery. The understanding of the cellular and

molecular events involved in this phenomenon could provide effective therapies not only to promote brain repair in stroke or seizures, but

also to facilitate functional improvement in depression or Alzheimer. In this context, many advances have been made, such as the implication

of different growth factors, membrane receptors, and most importantly diffusible messengers like nitric oxide (NO). We review here studies

in both normal and pathophysiological conditions that suggest a dual role for NO in adult neurogenesis and its relation to different

pharmacological strategies stimulating neurogenesis.

D 2005 Elsevier B.V. All rights reserved.

Theme: Development and regeneration

Topic: Genesis of neurons and glia

Keywords: Neurogenesis; NO; Stroke; Seizure; Depression; Alzheimer

Contents

. . . . . . . 1

. . . . . . . 2

. . . . . . . 2

. . . . . . . 2

. . . . . . . 2

. . . . . . . 3

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2. Neurogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2.1. Tissue localization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2.2. Regulation of neurogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2.3. Phases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3. NO and neurogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . 3

Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

1. Introduction

The formation of new neurons or neurogenesis is an

important phenomenon implicated in the development of the

nervous system; in the last years, it has been demonstrated

0165-0173/$ - see front matter D 2005 Elsevier B.V. All rights reserved.

doi:10.1016/j.brainresrev.2005.03.006

* Corresponding author. Fax: +34 91 3941463.

E-mail address: acardenas@ift.csic.es (A. Cardenas).

that neurogenesis also occurs in the adult nervous system

[17], and that it can be induced after brain injuries such as

seizures or stroke [36,51]. The discovery of the adult

neurogenesis has been considered as a possible new facet of

recovery that may translate into new treatments for stroke

[48]; in addition, its inhibition has been recently suggested

to be involved in the pathogenesis of depression and

Alzheimer [57,62], and different studies exist about its

s 50 (2005) 1 – 6

A. Cardenas et al. / Brain Research Reviews 50 (2005) 1–62

detrimental or beneficial effect after seizures [52,63].

Therefore, the study of adult neurogenesis is an exciting

and controversial field of research that has led to numerous

experimental studies and revisions [15,36,46].

Since its discovery, multiple functions for nitric oxide

(NO) in the nervous system have been described [19].

Moreover, the implication of NO in neuroprotection and

neurotoxicity has been widely studied, and its dual role after

brain ischemia has been recently reviewed [45]. In this

context, it seems clear that NO produced by the endothelial

isoform of nitric oxide synthase (eNOS) has a neuro-

protective role, while NO produced by the neuronal isoform

(nNOS) or by the inducible isoform (iNOS) leads to a

neurotoxic effect. This can be explained by the amounts of

NO generated and its timing of synthesis; while low levels

and very early synthesis of NO by eNOS are beneficial

through a local vasodilatation effect, high levels and more

sustained production of NO by nNOS or iNOS are neuro-

toxic mainly by oxidative stress.

Although with a different pattern, a dual role for NO also

exists in adult neurogenesis, since NO synthesized from

nNOS appears to decrease neurogenesis or to act as an

antiproliferative molecule [44,50,54] whereas the produc-

tion of NO from iNOS and eNOS seems to stimulate

neurogenesis [57,62,66]. The mechanism of this complex

regulation is discussed below.

2. Neurogenesis

2.1. Tissue localization

Two main neurogenesis loci have been identified in the

adult brain: the subventricular zone (SVZ), which lines the

lateral ventricles, and the subgranular zone (SGZ) of

dentate gyrus (DG). Newborn neurons from the SVZ travel

through the rostral migratory stream to the olfactory bulb

[39], and neurons that leave the SGZ migrate into the DG

granule cell layer [18]. Interestingly, it has been demon-

strated that SVZ is surrounded by differentiated neurons

expressing nNOS [43], and also this isoform has been

found in neuronal precursors in DG [28]. These findings

could be suggesting a role for NO in the main sites of adult

neurogenesis.

Moreover, although neurogenesis in the cortex cannot be

observed under physiological conditions, it has been

induced by targeted apoptosis of cortical pyramidal neurons

in mice [40] and in adult rats after transient middle cerebral

artery occlusion [31]. Since different NOS isoforms are

present in the cortex [45], NO could be regulating cortical

neurogenesis.

2.2. Regulation of neurogenesis

The regulation of neurogenesis is beginning to be under-

stood:DGcellneurogenesisappears tobeinfluencedbyfactors

such as aging, environmental stimulation, exercise, genetic

background, stress and afferent inputs to the dentate

granule cell layer [18]. It is known that neurogenesis is

modulated by both physiological [21] and pathological

stimuli [33,52,53], where newborn neurons can replace

neurons that have died because of an insult and thus

contribute to function recovery [49]. Seizures or cerebral

ischemia increases neurogenesis in both the adult DG and

SVZ-olfactory bulb pathway and, most importantly, the

new neurons are capable of integrating in the mature brain

[3,52]. Neurogenesis after seizures could be mediated by

molecules such as growth factors and neurotrophins, which

are expressed in this condition [26,27]. Also forebrain

ischemia increases the expression of several growth

factors, including basic fibroblast growth factor (bFGF),

brain-derived neurotrophic factor (BDNF), vascular endo-

thelial growth factor (VEGF) [32,37,59] and activated glia

is a potential source of cues that direct stroke-induced

neurogenesis [53]. In the case of VEGF, this factor could

be mediating the positive effect of NO in adult neuro-

genesis, since a decrease in VEGF transcripts in the

hippocampus of eNOS knockout animals has been

associated with a decrease in neurogenesis [57]. NO could

exert its effects on VEGF expression probably by the

activation of the protein kinase Akt and subsequent down-

stream effectors [12]. Also, BDNF expression has been

shown to be mediating the effects of eNOS in neurogenesis

after stroke [8].

2.3. Phases

The process of neurogenesis consists of three main

steps, which are precursor proliferation, migration, and

differentiation, integration and survival. (A) In precursor

proliferation, there are growth factors involved such as

bFGF [22,38,61], epidermal growth factor (EGF) [22,38]

and BDNF [4,55], all of them with mitogenic effect;

other molecules involved include neurotransmitters [1,5],

hormones [5,60], and drugs [9]. (B) Concerning the

neuroblast migration, there are attractive and repulsive

chemotropic factors, such as integrin subunits, ephrins

and reelin [10,23,29,47]. (C) Finally, and less under-

stood, is the molecular regulation of precursor differ-

entiation, integration and survival; however, several

studies suggest that astrocyte-derived cues act in these steps

[11,39,41].

It is important to remark here that most of the studies

on NO in adult neurogenesis are focused on the

modulation of proliferation, but the analysis of survival

rates could be also important [56] since NO is known to

be a bifunctional regulator of apoptosis [35]. In this

context, it has been shown that caspase inhibitors increase

the short-term survival of progenitor-cell progeny in the

adult rat DG following status epilepticus [13] and that

NO inhibits apoptosis by preventing caspase-3 activation

[34].

A. Cardenas et al. / Brain Research Reviews 50 (2005) 1–6 3

3. NO and neurogenesis

Different functions have been established for NO in the

nervous system, such as sensory motor functions [42],

control of cerebral blood flow [14] and neuroprotection and

neurotoxicity after cerebral ischemia [45]. NO is also

involved in synaptic formation and remodeling [25];

however, its role in neurogenesis has not been identified

until recently.

It has been demonstrated that NO is a physiological

inhibitor of neurogenesis in the adult mouse SVZ and in the

olfactory bulb [44]. The authors of this contribution had

previously described that the SVZ is surrounded by differ-

entiated neurons expressing nNOS and also that some

neuroblasts contain nNOS once they reach the OB

periglomerular area [43]; more recently, they have shown

that chronic nNOS inhibition enhances neurogenesis.

Indeed, the systemic administration of the selective nNOS

inhibitor 7-nitroindazole (7-NI) to adult mice produced a

dose- and time-dependent increase in the number of mitotic

cells in the SVZ, the rostral migratory stream (RMS), and

the olfactory bulb, but not in the DG. These results have

been confirmed by findings showing that when NO

production in the rat brain is suppressed either by intra-

cerebroventricular infusion of a NOS inhibitor, or by using a

null mutant neuronal NOS knockout mouse line, the number

of cells generated in the olfactory subependyma and DG is

strongly augmented, suggesting an antiproliferative effect

for NO [50,54]. Also, the inhibitory role of NO derived

from the nNOS on SVZ and DG neurogenesis has been

recently demonstrated in the context of cerebral ischemia

[58].

An opposite role has been found for eNOS- and iNOS-

derived NO. By using pharmacological or genetic

approaches, it has been demonstrated that NO synthesized

Fig. 1. Neurogenesis regulation by NO. DG: dentate gyrus; SVZ: subventricular

isoform of nitric oxide synthase (NOS); nNOS: neuronal isoform of NOS; eNO

details, see the text.

either by iNOS in DG after focal cerebral ischemia [66] or

by eNOS in SVZ also after focal ischemia [8] or in DG in an

adult model of depression [57] activates neurogenesis. The

biochemical events underlying ischemia-induced neuro-

genesis in DG are thought to involve the activation of

NMDA receptors [1,5], supported by the fact that there are

extensive data showing that iNOS expression is induced by

the activation of NMDA receptors after ischemia [6,30].

However, a very recent study about the effects of NO in DG

cell proliferation after seizures in adult rats has shown that

both nNOS- and iNOS-derived NO increase neurogenesis

[62].

While the antiproliferative effect of NO in adult brain

depends on the inhibition of cyclin-dependent kinases and

transcription factors by p53 and the Rb protein respectively

(reviewed in [20]), the proliferative effect of NO could be

mediated through an increase in the tissue levels of cGMP

[64,65]. This may explain the effects of some pharmaco-

logical approaches increasing neurogenesis such as the

administration of sildenafil, which is an inhibitor of

phosphodiesterase type 5 and therefore causes intracellular

accumulation of cGMP [65], of atorvastatin, which is

upregulating the eNOS isoform and thus increasing the

cGMP levels [7], or of NO donors which also increase cGMP

levels [64]. Moreover, the effect of cGMP on neurogenesis

could be related to the activation of cGMP-dependent protein

kinase type I, which has been described to enhance sensory

neuron precursor proliferation [16] (Fig. 1).

4. Conclusion

The experimental studies reviewed here indicate a dual

role for NO in adult neurogenesis; however, different

points remain unclear: Firstly, although most of the studies

zone; RMS: rostral migratory stream; OB: olfactory bulb; iNOS: inducible

S: endothelial isoform of NOS. ,: stimulation; –: inhibition. For specific

A. Cardenas et al. / Brain Research Reviews 50 (2005) 1–64

are showing an inhibitory role for nNOS-derived NO, a

proliferative effect of nNOS-derived NO has been described

in seizures. This discrepancy could be due to the different

dosage and administration patterns used for the nNOS

inhibitor or to a different activity and/or expression of the

NOS isoform; these issues need to be addressed in future

studies. Also, the different effects of NO synthesized by the

two calcium-dependent isoforms (eNOS and nNOS) in DG

has been described in terms of the spatial potential of eNOS

but not of nNOS to directly influence neural stem cells

because of the different distribution of these isoforms, but the

distribution is known to be wide and therefore more

conclusive studies are needed.

In addition, it has been demonstrated that only 20% of

the newly generated cells survive, resulting in a replace-

ment of 0.2% of the cells lost as a result of ischemia [2].

Therefore, in order to improve the functional recovery, it is

important not only to study the proliferation of precursors

but also their survival rate. In this context, the studies of

neurogenesis stimulation by different pharmacological

approaches related to NO should also take into account

the survival rates because NO is known to be a bifunc-

tional regulator of apoptosis [35]. Moreover, it must be

considered that cGMP produced by NO is involved not

only in increasing neurogenesis but also in promoting

functional recovery, an effect that could be related to the

implication of cGMP in the modulation of axonal guidance

and neurite outgrowth. Indeed, it has been demonstrated

that NO could stimulate neurite outgrowth from hippo-

campal neurons and PC12 cells exposed to nerve growth

factor (NGF) through a cGMP-dependent mechanism [24].

In conclusion, NO has been demonstrated to be an

essential mediator in adult neurogenesis, which could be

advantageous for the treatment of diseases such as stroke,

seizures, depression or Alzheimer depending on the neuro-

genesis contribution to the pathological process. In this

context, some pharmacological approaches related to NO

have been shown to be effective in neurogenesis stimulation

and improvement of functional recovery after stroke.

However, the clarification of different NOS isoforms

implicated that downstream effectors, effects on neuronal

plasticity or survival rates are needed.

Acknowledgments

This work was partly supported by grants from Spanish

Ministries of Health FIS-PI030304 (MAM) and Science and

Technology SAF2002-04487-C02-01 (IL). OH is a recipient

of a fellowship funded by (CAM) LocalMadrid Government.

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