INTRODUCTION

Prenatal or intrauterine period plays a critical role in normal physical, mental and

behavioural development of an individual. A vast number of factors such as genetic makeup,

epigenetic factors like nutrition, environmental toxins and stressful conditions (Van den Hove
et al., 2005; Bowman et al., 2004) play a major role on normal growth during intrauterine
development. In most of such instances, affect of such insults will be carried to perinatal and
young age and even to whole lifespan of individual (Koehl et al., 2001). Though any system
of body may be the target of flawed development, nervous system is the main organ of faulty
development.

Substantial body of evidences indicate that prenatal stress significantly affect the
development of brain and the organization of behaviour especially cognition (Yang et al.,
2006; Lemaire et al., 2000). It has a long-lasting effect on adult cognition in humans (Keelan
et al., 1992) and animals (Darnaudery et al., 2006). Prenatal stresses of different nature and
duration applied during various gestational periods have shown to decrease the locomotor
activity (Gue et al., 2004) and immobility in the constrained swim test (Drago et al., 1999).
Prenatal stress is reported to increase the anxiety like behaviour in elevated plus maze and as
well as in open field (Kohman et al., 2008). Gestational stress is also reported to decrease the
spatial learning and memory in T-maze (Son et al., 2006), water maze (Li et al., 2008), Y-
maze (Darnaudery et al., 2006) and passive avoidance test (Meunier et al., 2004). Cause for
these behavioural abnormalities is still unclear. But, there are many reports suggesting the
possible mechanisms like altered hypothalamo-pituitary-adrenal (HPA) axis, increased brain
corticosterone level, altered neurotransmitters and decreased neuronal cell proliferations
(Kawamura et al., 2006, Fujioka et al., 2006; Lemaire et al., 2006) may be involved during
prenatal development. Prenatal stress-induced defective neurogenesis and neuronal
proliferation during neonatal development is not studied extensively. Such neuronal
dysfunction can interfere in cognition in later part of the life. The studies involving the
prevention of defective neurogenesis and neuronal proliferation due to prenatal stress are also
not well documented.

Growing data from experimental models and human brain studies suggest that
oxidative stress may play an important role in various neurological disorders, such as
epilepsy, Alzheimer’s disease, Parkinson’s disease, stroke, cerebral ischemia, multiple
sclerosis, Huntington’s chorea, tardive dyskinesia, and amyotrophic lateral sclerosis (Bondy,
1995). The brain is especially vulnerable to oxidative damage because of brain’s high oxygen

Neuroprotective effects of resveratrol against prenatal stress in rats

 INTRODUCTION

consumption, abundant lipid contents and the relative paucity of antioxidant enzymes as
compared with other tissues (Skaper et al, 1999). Moreover, brain has a high ratio of
membrane surface area to cytoplasmic ratio and extended axonal a morphology prone to
injury. Oxygen free radicals impair capillary endothelial cell mechanisms that in turn disrupt
electrolytes and water homeostasis and membrane fluidity characteristics in brain. Prenatal
stress is also known to cause neuronal damage in the offspring (Kawamura et al., 2006,
Fujioka et al., 2006). But, it is unknown whether the neuronal damage in prenatal stressed
offspring is due to increase oxidative stress. Hence various oxidant and antioxidant
parameters were estimated in the offspring brain to find a role of prenatal stress induced
neuronal damage and oxidative stress.

Although there are a relatively large amount of literatures on the pharmacological

treatment of stress disorders in general populations, the number of trials on pregnant or breast
feeding women is very small, because of the ethical issues in studying these populations.
Information on the safety of anti-anxiety and anti-depressant drugs during pregnancy is
limited, there for these drugs are not commonly used during pregnancy to prevent stress.
Hence the recent research focusing on dietary supplements which are safe and cost effective
to alter stress effects, hormonal modulation, and optimal regulation of emotion/attention in
infants.

Resveratrol is reported effective against neuronal cell dysfunction and cell death (Jin
et al., 2008). There are many reports suggesting that resveratrol enhances cognition in rats
(Schmatz et al., 2009; Kumar et al., 2007). Resveratrol exerts neuroprotective properties by
up regulating several detoxifying enzymes, most of which are iron proteins (Qui-Hai Gong et
al., 2010). Resveratrol treatment immediately after traumatic brain injury reduces oxidative
stress and lesion volume (Ates et al., 2007). Resveratrol is known to exert its neuroprotective
effects through free radical scavenging activity and its nitric oxide promoting properties in
ischemic conditions (Blanchet et al., 2008).

With these findings there is reason to believe that resveratrol by its antioxidant or
other unknown mechanism could reverse the neurotoxic effects at behavioural, biochemical
and histological levels in all age groups. Hence the present study was undertaken to evaluate
the neuroprotective effect of resveratrol against prenatal stress. We investigated the safety of
the use of resveratrol in pregnancy by screening mortality rate, gestational length and early
physical developments. We further evaluated the role of prenatal stress, resveratrol and their

Neuroprotective effects of resveratrol against prenatal stress in rats

 INTRODUCTION

combinations on postnatal neurogenesis by using doublecortin neuronal marker. In this study

we also evaluated the effects of prenatal resveratrol treatment on long term adult behavioural
activities, especially cognition using standard rodent behavioural models (water maze and
passive avoidance test). In determining the possible mechanism (oxidative damage) involved
in prenatal stress-induced neurotoxicity, we investigated standard biochemical analysis like
estimation of lipid peroxidation, advanced oxidative products of protein, reduced glutathione,
glutathione reductase, superoxide dismutase and total antioxidants.

This knowledge is of importance as this provided the basis for cognitive and
behavioural disorders caused due to hippocampal damage in children of mothers who work
and function under duress and stressed conditions. This study also highlighted on usage of
resveratrol during pregnancy. The outcome of this study is of immense clinical importance in
dealing with prenatal stress induced neurotoxic effects in offspring.

Neuroprotective effects of resveratrol against prenatal stress in rats