its a part of debate

1. Ketamine as a neuroapoptotic
agent
Presenter – Dr. Aparna Jayara(pg-2nd yr)
Moderator- Dr. Subhro Mitra(AP)

2. HISTORY
• The history of Ketamine is well known and dates back to 1962 when it was
first synthesized by American scientist Calvin Stevens at the Parke Davis
Laboratories.
• As the history of Ketamine began, it was initially named CI-581 and
developed as a derivative of PCP, synthesized in 1926, as an anesthetic
drug which acts, primarily, as an NMDA receptor antagonist.
• After being patented for human and animal use in 1966, by Parke-Davis
Laboratories, Ketamine became available, by prescription, in 1969, in the
form of Ketamine Hydrochloride and under the name of Ketalar. It was
officially approved for human consumption by the United States Food and
Drug Administration in 1970 and was administered to soldiers during the
Viet Nam War as a field anesthetic.

4. • It is N-methyl –D-aspartate (NMDA ) antagonist
,commonly available as aqueous solution of the
hydrochloride salt with a pka of 7.5
• Racemic mixture of s(+) ketamine and L(-)
ketamine enantiomer
• The s(+) available in some countries has greater
affinity and selectivity for NMDA receptor and
has more analgesic potency than rest .
• Water soluble agent with a molecular weight of
274
• Highly lipophilic and easily crosses the BBB.

5. pharmacology
• Pharmacokinetics- Ketamine is metabolized by
hepatic microsomal enzymes. The major pathway involves N-
demethylation to form norketamine (metabolite I), which is
then hydroxylated to hydroxynorketamine, which is further
conjugated to water-soluble glucuronide derivatives and
excreted in the urine.
• Hypnotic effect begins in 30-60 seconds
when administered in a dose of 1-2
mg/kg i.v.
• the peak effect after i,.m. at 10-15
minutes
oral administration at 15-30 min
• In addition to the intravenous and
intramuscular
routes, ketamine may be administered
rectally (10 mg/kg), orally (6 to 10
mg/kg), or intranasally (3 to 6 mg/kg).
• Vd-3l/kg,
• redistribution T1/2 =7-15 min,
• clearance 15 ml/kg/min,
• elimination t1/2 =2-3 hrs.

6. • CNS - Ketamine produces dose-related unconsciousness and analgesia.
Ketamine acts at multiple receptors, including the NMDARs, opioid receptors,
and monoaminergic receptors.
• The most important action of ketamine is inhibition of NMDARmediated
glutamergic input to the GABA-ergic system that leads to changing excitatory
activity in the cortex and limbic system that in the end results in
unconsciousness. The NMDAR has high expression in the temporal cortex,
hippocampus, basal ganglia, cerebellum, and brainstem, all regions
significantly affected by ketamine
The anesthetized state has been termed dissociative anesthesia because
patients who receive ketamine alone appear to be in a cataleptic state, in
contrast to other states of anesthesia that resemble normal sleep.
• Patients anesthetized with ketamine have profound analgesia, but they keep
their eyes open and maintain many reflexes.
• Although interindividual variability is great, plasma levels of 0.6 to 2 μg/mL
are considered the minimum concentrations for general anesthesia; children
may require slightly higher plasma levels (0.8 to 4 μg/mL)

7. • The primary site of CNS action of ketamine seems
to be the thalamoneocortical projection system.
The drug selectively depresses neuronal function
in parts of the cortex (especially association
areas) and thalamus while stimulating parts of
the limbic system, including the hippocampus.
• This process creates what is termed a functional
disorganization of nonspecific pathways in
midbrain and thalamic areas.
•

8. • Ketamine increases cerebral metabolism, CBF, and ICP. Because of its
excitatory CNS effects, which can be detected by generalized EEG
development of theta wave activity and by petit mal seizure-like activity in
the hippocampus, ketamine increases CMRO2. . With the rise in CBF and
the generalized increase in sympathetic nervous system response, ICP
increases after ketamine use

9. KETAMINE MEDIATED
NEUROAPOPTOSIS
• What is neuroapotosis?
• Neuroapoptosis is a natural process of neuronal cell death
believed integral to normal mammalian brain development
• During std fetal and neonatal system development , an axis
of neuron is produced and as many as 50-70% later
undergo internal signals to commit suicide
• In animal models, exogenous substances can accelerate this
process of prgrammed cell death by blockade of NMDA
receptor or stimulation of GABA receptors.
• The resulting CNS damage is evident on neuropathological
examination
• The most commonly implicated and most research
precipitant is ketamine

12. 1 Blockade of NMDA receptors and apoptotic
neurodegeneration in the developing brain.
• Programmed cell death (apoptosis) occurs during normal development of the central nervous
system. However, the mechanisms that determine which neurons will succumb to apoptosis
are poorly understood. Blockade of N-methyl-D-aspartate (NMDA) glutamate receptors for
only a few hours during late fetal or early neonatal life triggered widespread apoptotic
neurodegeneration in the developing rat brain, suggesting that the excitatory
neurotransmitter glutamate, acting at NMDA receptors, controls neuronal survival. These
findings may have relevance to human neurodevelopmental disorders involving prenatal
(drug-abusing mothers) or postnatal (pediatric anesthesia) exposure to drugs that block
NMDA receptors.
• Science. 1999 Jan 1;283(5398):70-4.

13. 2 Pathological changes induced in
cerebrocortical neurons by
phencyclidine and related drugs.
• Science. 1989 Jun 16;244(4910):1360-2.
• Olney JW1, Labruyere J, Price MT.
• Author information
• Abstract
• Phencyclidine (PCP), a dissociative anesthetic and widely abused psychotomimetic drug, and MK-801, a potent
PCP receptor ligand, have neuroprotective properties stemming from their ability to antagonize the excitotoxic
actions of endogenous excitatory amino acids such as glutamate and aspartate. There is growing interest in the
potential application of these compounds in the treatment of neurological disorders. However, there is an
apparent neurotoxic effect of PCP and related agents (MK-801, tiletamine, and ketamine), which has heretofore
been overlooked: these drugs induce acute pathomorphological changes in specific populations of brain neurons
when administered subcutaneously to adult rats in relatively low doses. These findings raise new questions
regarding the safety of these agents in the clinical management of neurodegenerative diseases and reinforce
concerns about the potential risks associated with illicit use of PCP.
• In 1989, Olney et al. discovered that neuronal vacuolation and other cytotoxic changes ("lesions") occurred in
brains of rats administered NMDA antagonists, including PCP, MK-801 (dizocilpine) and ketamine.[2]

14. 3 Ketamine Anesthesia during the First Week of Life
can Cause Long-Lasting Cognitive Deficits in Rhesus
Monkeys
• . M. G. Paule,1 M. Li,1 R. R. Allen,2 F. Liu,1 X. Zou,1 C. Hotchkiss,3 J. P. Hanig,4 T. A.
Patterson,1 W. Slikker, Jr.,1 and C. Wang1
• l Published in final edited form as:
• Neurotoxicol Teratol 2011 ; 33(2): 220–230. doi:10.1016/j.ntt.2011.01.001
In the present study, six monkeys were exposed on PND 5 or 6 to intravenous
ketamine anesthesia to maintain a light surgical plane for 24 hrs and six control
animals were unexposed
. At 7 months of age all animals began training to perform a series of cognitive
function tasks
around 10 months of age, control animals significantly outperformed (had higher
training scores than)
For animals now over 3 and one-half years of age, the cognitive impairments continue
to manifest in the ketamine-exposed group as poorer performance
There are also apparent differences in the motivation of these animals .
These observations demonstrate that a single 24-hr episode of ketamine anesthesia,
occurring during a sensitive period of brain development, results in very long-
lasting deficits in brain function in primates and provide proof-of-concept that
general anesthesia during critical periods of brain development can result in
subsequent functional deficits. Supported by NICHD, CDER/FDA and NCTR/FDA

15. 4 KETAMINE-INDUCED NEUROAPOPTOSIS IN THE
FETAL AND NEONATAL RHESUS MACAQUE BRAIN
• Anesthesiology. 2012 February ; 116(2): 372–384. doi:10.1097/ALN.0b013e318242b2cd
• Background--Exposure of rhesus macaque fetuses for 24 h, or neonates for 9 h, to ketamine
anesthesia causes neuroapoptosis in the developing brain. This study further clarified the
minimum exposure required for, and the extent and spatial distribution of, ketamine-induced
neuroapoptosis in rhesus fetuses and neonates.
• Method--Ketamine was administered by intravenous infusion for 5 h to postnatal day 6
rhesus neonates, or to pregnant rhesus females at 120 days gestation (full term = 165
days). Three hours later, fetuses were delivered by caesarian section, and the fetal and
neonatal brains were studied for evidence of apoptotic neurodegeneration, as determined by
activated caspase-3 staining.
• Results---Both the fetal (n = 3) and neonatal (n = 4) ketamine-exposed brains had a significant
increase in apoptotic profiles compared to drug-naive controls (fetal n = 4; neonatal n = 5).
Loss of neurons due to ketamine exposure was 2.2 times greater in fetuses than in neonates.
The pattern of neurodegeneration in fetuses was different from that in neonates, and all
subjects exposed at either age had a pattern characteristic for that age.
• Conclusion---The developing rhesus macaque brain is sensitive to the apoptogenic action of
ketamine at both a fetal and neonatal age, and exposure duration of 5 h is sufficient to induce
a significant neuroapoptosis response at either age. The pattern of neurodegeneration
induced by ketamine in fetuses was different from that in neonates, and loss of neurons
attributable to ketamine exposure was 2.2 times greater in the fetal than neonatal brains.
• Published in final edited form as:
• Ansgar M. Brambrink, M.D., Ph.D.* [Professor], Alex S. Evers, M.D.† [Professor &
• Chairman], Michael S. Avidan, M.B.B.Ch., F.C.A.S.A.‡ [Associate Professor], Nuri B.
• Farber, M.D.§ [Professor], Derek J. Smith, B.A.$ [Research Associate], Lauren D. Martin,
• V.D.% [Staff Veterinarian], Gregory A. Dissen, Ph.D.# [Staff Scientist], Catherine E. Creeley,
• Ph.D.ψ [Instructor], and John W. Olney, M.D.δ [Professor]

16. 5 Role of glycogen synthase kinase-3β in ketamine-induced developmental
neuroapoptosis in rats.
Liu JR1, Baek C, Han XH, Shoureshi P, Soriano SG
• Source: https://www.ncbi.nlm.nih.gov/pubmed/23533250
• Br J Anaesth. 2013 Jun;110 Suppl 1:i3-9. doi: 10.1093/bja/aet057. Epub 2013 Mar 26
• BACKGROUND: -Ketamine-induced neuroapoptosis has been attributed to diverse stress-related
mechanisms. Glycogen synthase kinase-3β (GSK-3β) is a multifunctional kinase that is active in neuronal
development and linked to neurodegenerative disorders. They hypothesized that ketamine would
enhance GSK-3β-induced neuroapopotosis, and that lithium, an inhibitor of GSK-3β, would attenuate this
response in vivo.
• METHODS: -Protein levels of cleaved caspase-3, protein kinase B cyclin D1 (AKT), GSK-3β, and were
measured in post-natal day 7 rat pups after 1.5, 3, 4.5, and 6 h exposure to ketamine. A cohort of rat pups
was randomized to a 6 h exposure to ketamine with and without lithium. Neuroapoptosis was measured
by cleaved caspase-3 and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling
staining by immunohistochemistry. Protein levels of cleaved caspase-3 and -9 and the total and
phosphorylated forms of AKT, GSK-3β, and cyclin D1 (cell cycle protein) were also measured.
• RESULTS: Ketamine produced a duration-dependent increase in cleaved caspase-3 and cyclin D1, which
corresponded to decreases in phosphorylated AKT and GSK-3β. Co-administration of lithium with
ketamine attenuated this response.
• CONCLUSIONS: Ketamine-induced neuroapoptosis is associated with a temporal decrease in GSK-3β
phosphorylation, and simultaneous administration of lithium mitigated this response. These findings
suggest that GSK-3β is activated during this ketamine-induced neuroapoptosis

17. 6 Ketamine-Induced Neurotoxicity
and Changes in Gene Expression in
the Developing Rat BraiNFang Liu, Merle G Paule, Syed Ali, and Cheng Wang*
• Author information ► Article notes ► Copyright and License information ►
• This article has been cited by other articles in PMC.
• Go to:
• Abstract
• Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, is widely used for analgesia and anesthesia in
obstetric and pediatric practice. Recent reports indicate that ketamine causes neuronal cell death in developing
rodents and nonhuman primates. The present study assessed the potential dose- and time-dependent neurotoxic
effects and associated changes in gene expression after ketamine administration to postnatal day 7 (PND-7) rat
pups.
• Pups were exposed to ketamine subcutaneously at doses of 5, 10, or 20 mg/kg, in one, three or six injections
respectively. Control animals received the same volume of saline at the same time points. The animals were
sacrificed 6 h after the last ketamine or saline administration and brain tissues were collected for RNA isolation
and histochemical examination. Six injections of 20 mg/kg ketamine significantly increased neuronal cell death in
frontal cortex, while lower doses and fewer injections did not show significant effects. The ketamine induced cell
death seemed to be apoptotic in nature. In situ hybridization demonstrated that NMDA receptor NR1 subunit
expression was dramatically increased in the frontal cortex of ketamine treated rats. Microarray analysis revealed
altered expression of apoptotic relevant genes and increased NMDA receptor gene expression in brains from
ketamine treated animals. Quantitative RT-PCR confirmed the microarray results. These data suggest that
repeated exposures to high doses of ketamine can cause compensatory up-regulation of NMDA receptors and
subsequently trigger apoptosis in developing neurons
• Curr Neuropharmacol. 2011 Mar; 9(1): 256–261
• Fang Liu, Merle G. Paule, Syed Ali and Cheng Wang

18. 7 Pediatric anesthetic risk: Ketamine
may damage children's learning
ability and memory
• Date: July 19, 2013
• Source: Neural Regeneration Research
• Published in science daily
• Summary: Recent studies have found that anesthesia drugs have
neurotoxicity on the developing neurons, causing learning and
memory disorders and behavioral abnormalities. Ketamine is
commonly used in pediatric anesthesia. A clinical retrospective
study found that children under 3 years old who received a long-
time surgery, or -- because of surgery -- require ketamine
repeatedly, exhibited learning and memory disorders and
behavioral abnormalities when they reached school-age

19. 8 Pathophysiology of Ketamine
Neurotoxicity
• December 2016 with 39 ReadsDOI: 10.1016/B978-0-12-800212-4.00052-2
In book: Neuropathology of Drug Addictions and Substance Misuse, pp.563-57
• A growing number of evidences in rodents and nonhuman
primates have indicated that exposure to repeat doses of
ketamine can induce neuroapoptosis and damage in the
developing brain, mainly hippocampal neurodegeneration,
causing persistent learning and memory impairment.
However, the precise mechanisms of ketamine
neurotoxicity are not completely understood. It is indicated
that the upregulation of the NMDA type of glutamate
receptors is responsible from ketamine-induced
neurotoxicity by causing to a toxic accumulation of
intracellular calcium. Neuronal apoptosis via reactive
oxygen species-mediated mitochondrial pathway plays
pivotal role in the ketamine neurotoxicity. Ketamine also
alters the cortical neurogenesis of neural stem progenitor
cells through a different manner.