LEVETIRACITAM & cognition in sporadic dementia of Alzheimers type in rats AA Nawar, IE Darwish, CA Ismail Alzheimers disease (AD) Progressive neurodegenerative disorder Most common dementia in elderly (70 80 %) Irreversible loss of neurons, mainly in neocortex & hippocampus Prevalence rates Alzheimers disease (AD) Progressive neurodegenerative disorder Most common dementia in elderly
(70 80 %) Irreversible loss of neurons, mainly in neocortex & hippocampus AD is a leading cause of death Sepsis, Pneumonia, Nutritional deficiencies & Trauma AD disabilities & patients care lead to high socioeconomic burden Inflammation & Pathogenesis Oxidative stress AP AP aggregation Hyper-phosphorylation of tau protein Epilepsy
& Alzheimers AD patients have an increased risk of developing seizures An estimated 10 to 22 % of AD patients develop unprovoked seizures with higher rates in familial & early-onset cases About 21% of In sporadic sporadic AD patients
have AD, the atpresence least oneof unprovoked ApoE4 allele, clinically predisposes apparent seizure non-demented carriers for epileptogenesi s (two-fold increase risk) Causal relationship High lev els of A were
sufficien t to elicit epilepti form activity & seizures Marker of more severe or aggressive AD Greater Can occ seizures ur early, or Seizures can duration & even coincide everity b
s e with he correlated increase t onset of nce of a h c with more cognitiv e impaired severe decline cognition dementia A peptide Learning & memory deficits
Neuronal hyperexcitability Cell death & cognitive declineCyclical Activitydependant modelamyloid plaque of excitotoxic Seizur neurodegeneration Excess Facilitating A release es Shift from - to
-secretase cleavage of APP synaptic Glutamate release Seisure treatment in AD Seizure treatment is mandatory Responsive to monotherapy treatment Antiepileptic drugs (AEDs) vary in their effect on cognition
AED s & cognitive impairment AEDs can Some effective reduce AEDs are cognitive associated with a dysfunction by considerable controlling degree of seizures cognitive impairment Patients with existing cognitive problems, like AD patients, may be at greater risk using
drugs with adverse cognitive effects AED s & cognitive impairment Aim of Study Gabapentin Levetiraceta Theirmpossible utility to & modulate cognitive versus performance Old AEDs ?
Carbamazepin e Colchicine The possible mechanism ofON action underlying this modulation SDAT in reference to Donepe zil Levetiracetam promising effect AChE is Marker of extended cholinergic neuron loss Noncholinergic/
Peripheral non-site anionic catalytic Future function Promotes amyloid fibril target aggregation AChE activity in AD Cholinergic/ catalytic function Cholinestera ACh Main se inhibitors target hydrolysis
Decrease ACh level Levetiracetam promising effect i ta c a r ti e v e L m AD Epileps y Pyrrolidine molecules
Materials & Methods Paxinos and Watson atlas 1.8 mm lateral to sagittal suture Stereotaxic Coordinates 3.6 mm beneath cortical surface 0.8 mm posterior to bregma Experimental Design Contro Treated l-non
treated group group Levetiracetam Normal Control 100 mg/kg/day aCSFinjected Untreated AD Gabapentin 60 mg/kg/day 1ml of 1% vehicle Carbamazepine
Donepezil icv injection of 10 l of l aCSF 100 mg/kg/day icv injection of 10 l of l of colchicine 8 2 mg/kg/day Induction of Sporadic dementia of Alzheimers type Days 1 13 14
21 22 25 26 Maze Probe Step-through Maze Maze Maze Probe Step-through retention (Retrieval) passive Maze Maze retention (Retrieval) acquisition test retention passive 1st RL retention Trial avoidance acquisition
test (IAL) test 1st test RL 2nd RL Trial avoidance task test 2nd RL test (IAL) task anesthetized i.p anesthetized with thiopentali.p with thiopental sodium sodium 15 g of colchicine g of colchicine 15 g of colchicine ginof dissolved 5 colchicine g of colchicine l aCSF was dissolved
in 5 g of colchicine l aCSF was injected bilaterally into the injected bilaterally the lateral ventricle (5 g of colchicine linto /side) lateral ventricle (5 g of colchicine l/side) ISTL ISTL STRL STRL MWM task
1. Hidden platform test (testing for retention of learned tasks) 2. Probe test (second estimate of strength & accuracy of spatial memory) 3. Visible platform test (testing rats visual acuity) Open field arena Gross behavioural & locomotor activities Immediately before the MWM task, the rats spontaneous motor activities were assessed in an open field arena On day 27, animals were sacrificed 1
13 Days 14 21 22 25 26 Malondialdehyd Malondialdehyd e e (MDA) (MDA) Reduced Reduced Glutathione Glutathione (GSH) (GSH) Acetylcholinester
Acetylcholinester ase enzyme ase enzyme (AChE) specific (AChE) specific activity activity Brain-derived Brain-derived neurotrophic neurotrophic factor (BDNF ) factor (BDNF ) Prefrontal Cortex Hippocampus 27
(M W In it ia l a c q u is it io n la t e n c y Effect of studied drugs on IAL in MWM in icv-colchicine injected rats (second) 100 90 80 70 60 50 40 30 20 10 0 1 s t r e t e n t io n la t e n c y ( M W Effect of studied drugs on 1st RL in MWM in icv-colchicine injected rats (second)
90 80 70 60 50 40 30 20 10 0 2nd retention latency (MWM) task) Effect of studied drugs on 2nd RL in MWM in icv-colchicine injected rats (second) 80 70 60 50 40 30 20
10 0 Normal control IA aCSF-injected IB untreated AD IC Gabapentin IIA Levetiracetam IIB Carbamazepine
IIC Donepezil IID Effect of studied drugs on escape latency to the hidden platform in MWM during the three days of training sessions in icv-colchicine injected 120 (second) Time in second 100 80 Normal IA aCSF-injected IB Untreated AD IC Gabapentin IIA Levetiracetam IIB
Carbamazepine IIC Donepezil IID 60 40 20 0 IAL 1st RL 2nd RL P e r c e n t o f ti m e s p e n t i n N o r t h - W e s t q u a d r a Effect of studied drugs on percent of time spent in target quadrant (N-W) in MWM in icvcolchicine injected rats 50 45 40
35 30 25 20 15 10 5 0 R e t e n ti o n l a t e n c y i n p a s s i v e a v o i d a n c e t Effect of studied drugs on RL in the stepthrough passive avoidance task in icv-colchicine injected rats 350 300 250 200 150 100 50 0
C o n ce n tr a ti o n o f M D A Effect of studied drugs on hippocampal and PFC MDA in icv-colchicine injected rats (nmol/g tissue) 600 500 400 300 200 100 0 N o rm al co n trol IA aCSF-i n jected IB u n treated AD
IC hippocampus Gab ap en tin IIA Levetiracetam prefrontal cortex IIB Carb am azep in e IIC Do n ep ezi l IID C o n c e n t r a ti o n o f r e d u c e d g l u t a t h i o n e i n m
Effect of studied drugs on hippocampal and PFC GSH in icv-colchicine injected rats 180 hippocampus prefrontal cortex 160 140 120 100 80 60 40 20 0 N ormal c ontrol IA
aCSF-i njec ted IB untreate d AD IC G abapentin IIA L evetirac etam IIB Carbamaz epine IIC Donepezil II D
A c e t y l c h o l i n e s t e r a s e s p e c i fi c a c ti v i t y i n mol/min/0.1 g tissue m o l / Effect of studied drugs on hippocampal and PFC AChE activity in icv-colchicine injected rats 140 120 100 80 60 40 20 0 hippocampus prefrontal cortex C o n c e n t r a ti o n o f B D N F i n h i p p o c a m p u s a n d p r Effect of studied drugs on hippocampal and
PFC BDNF in icv-colchicine injected rats 800 hippocampus prefrontal cortex 700 600 500 400 300 200 100 0 No rm al con tr ol IA aC SF-i n jec ted IB
u nt reated AD IC Gab ap en tin I IA Levetiracetam II B C arb am azep i ne IIC D on ep ezi l IID Conclusions Levetiracetam & gabapentin improved
cognitive function & obviously protected both hippocampus & PFC from the deleterious effects of colchicine in rat model of SDAT to the contrary to carbamazepine This might be mainly due to their cholinergic neurotrophic modulation, and antioxidant potential, although their effect on AChE activity was variable Conclusions Levetiracetam cognitive improvement was nearly comparable to that of donepezil making it the most favourable AED to be used in AD-like dementia THANK YOU
