SYNOPSIS

For approval of topic of the thesis to be submitted in the partial

fulfillment of the requirement for the degree of Master of
Pharmacy in Pharmacology

Evaluation of antidepressant potential of

agmatine in diabetes induce depression in rats

By
Nitin P. Nimje
B.Pharm

Guide
Mr. B. G. Taksande
M.Pharm

SMT.KISHORITAI BHOYAR COLLEGE OF PHARMACY,

New Kamptee, Nagpur, Maharashtra, 441002 (India)
2013-2014
Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur.
Introduction:-

Diabetes is a chronic metabolic disorder characterized by

hyperglycemia
as a result of impaired insulin regulatory mechanism, which
often results in neuropsychological complications such as
depression.
Studies have reported the prevalence rates of depression of 24
30% in
diabetic individuals with significantly increased risk of morbidity
and mortality. Pharmacological reports manifest that the altered
physiological processes such as elevated glucose oxidation,
insulin
deficiency and/or sensitivity and adaptive neurocellular responses
as a
consequence of diabetes may cause depression.
The monoamine serotonin is a well established neurotransmitter
involved in the pathophysiology of depression. The classic
monoamine
hypothesis states that monoamine imbalance or more specifically
neurotransmitter deficiency in certain areas in the brain
develops depression
Insulin as a peptide hormone and neuromodulator has been
known
to have diverse functions in the brain. Previous studies have
demonstrated
the role of insulin in improving cognitive functions including
learning and memory and in attenuating the neuronal damage
associated
with neurodegenerative diseases. Literary data give evidence that
the administration of insulin causes a sequential increase in the
concentration of tryptophan(a serotonin precursor) and serotonin
in the rat brain. In addition, a growing body of evidence suggests
the activity of insulin in depression comorbid with diabetes.
Behavioral studies have shown that treatment with insulin
produces antidepressant effects in streptozotocin (STZ) induced
diabetes such as a decreased duration of immobility in rat tail
suspension

test (TST) and rat forced swim test (FST). Furthermore,

insulin increases reward behavior in STZ diabetic mice subjected
to an
intracranial self stimulation testing paradigm. While insulin
deficiency
leads to depression like symptoms in STZ-diabetic rats.
However, the neurochemical mechanism underlying these effects
is
poorly understood.
Agmatine is a polycationic amine synthesized via decarboxylation
of L-arginine by argininedecarboxylase(ADC) and is defined as a
neuromodulator. In mammalian brains agmatine is expressed in
some regions like as hypothalamus, hippocampus, cortex, locus
ceruleus, Raphe nucleus and forebrain. Agmatine has been
reported to have some neuroprotective effects against MPTP
neurotoxicity, spinal cord ischemia, restraint-induced structural
changes in the brain,LPS and scopolamine induced memory
impairment. Additionally it is known to exert antidepressant,
anxiolytic, anti-tumor cell proliferative and anticonvulsive effects.

Objective:
To study the influence of intra-hippocampal agmatine on ketamine induced
memory impairment in rats and involvement of 2-adrenergic receptors in it.
Plan of work:
1. Induction of schizophrenia in rats by chronic ketamine administration and
assessment of memory in inhibitory avoidance

2. Dose dependant effect of agmatine and 2-adrenergic receptors ligand on

memory of ketamine treated rats
3. Influence of 2-adrenergic receptors ligands on the action of agmatine in
ketamine treated rats

Material and method:Animal:- Adult male Sprague-Dawley rats(240-260 g) will be group housed in
acrylic cages (24x17x12 cm) under ambient room temperature (25+ 2 c ) And
relative humidity (50 + 5%),maintained at 12:12 h dark-light cycle (lights on at
07:00 h).Food and water will be available ad libitum. The experimental procedure
will be performed as per the protocol approved by Institutional Animal and Ethical
Committee according to the guidelines of CPCSEA. Every possible effort will be
made to reduce the suffering of animals in all the experimental design.
Drugs:- Agmatine Sulphate, Clonidine, Yohimbine, Ketamine
Induction of Schizophrenia:-Schizophrenia in rats will be induced by injections
of ketamine:- Ketamine is NMDA antagonist, and its chronic administration will
lead to psychosis in rodents. Rat will be injected with ketamine (30 mg/kg I.P)
twice daily for 7 days.
Assessment of memory:-Apparatus: Inhibitory Avoidance Apparatus
Training :- Rats will be allowed to habituate in experimental room for 30 min prior
to experiments. All experiments groups will be first habituated to apparatus. Each
animal will be gently placed in light compartment for 10 sec, after which the
guillotine door will be lifted and the latency with which animal crosses to the dark
compartment will be recorded. Animals that wait more than 60 sec to cross to other
side will be eliminated from the experiment. Once animal crosses with all four
paws to dark compartment, the door will be closed and rat will be taken from the
dark compartment into the cage. The Habituation trail will be repeated after 30 min
and will be followed after same interval by acquisition trail during which the
guillotine door will be closed and foot shock (50 Hz, 1.5 sec, 2.5 mA) will be
delivered immediately after the rat has entered the dark compartment. After 10 sec,

rat will be removed from apparatus and place temporarily into the home cages
(zarrindes et al., 2002).
Testing (retention test):-Twenty four hours after training, retention test will be
performed to determine step through latency. Each animal will be placed in the
light compartment for 10 sec, door will be opened, and the step through latency
will be measured for entering into dark compartment. The test session ends when
the animal remains in the light compartment for 300 sec. During this session no
electric shock will be applied.
Possible outcome
This study may provide novel therapeutic options for treatment of memory
impairment associated with schizophrenia and could also project agmatine in the
treatment of schizophrenia and associated complications.
Reference
[1] Ali S, Stone MA, Peters JL, Davies MJ, Khunti K. The prevalence
of comorbid depression
in adults with type 2 diabetes: a systematic review and meta
analysis. Diabet
Med 2006;23:116573.
[2] Goldney RD, Phillips PJ, Fisher LJ,Wilson DH. Diabetes,
depression, and quality of life
a population study. Diabetes Care 2004;27:106670.
[3] Roy T, Lloyd CE. Epidemiology of depression and diabetes: a
systematic review.
J Affect Disord 2012;142:S8S21.
[4] Park M, KatonWJ,Wolf FM. Depression and risk ofmortality in
individualswith diabetes:
a meta-analysis and systematic review. Gen Hosp Psychiatry
2013;35:21725.
[5] Talbot F, Nouwen A. A review of the relationship between
depression and diabetes
in adults: is there a link? Diabetes Care 2000;23:155662.
[6] Egede LE, Nietert PJ, Zheng D. Depression and all-cause and
coronary heart disease
mortality among adults with and without diabetes. Diabetes Care
2005;28:133945.

Student
Mr. Abhinav Bawiskar
Chopde

Guide
Dr.

C.

T.