Memory Impairment

1. AMNESIA(Role of PAF & Benzodiazepine Receptors)
Prof. (Dr.) Kamal Kishore Maheshwari
Department of Pharmacy, M.J.P.
Rohilkhand University, Bareilly-243006
(Uttar Pradesh).

2. Amnesia-It is a severe disruption of memory
without any deficit in intelligence, attention,
perception or judgment (Markowitsch, 1988;
Lucchelli et al., 1997).

3. Classification of Amnesia
 Anterograde amnesia-is impairment to
store new memories. Anterograde amnesia is known
to impair memory for facts or events, but it does not affect memory
for skills/habits. Transient global/temporary amnesia is a type of
anterograde amnesia of short duration of one day or less. Certain
drugs such as benzodiazepines and anticholinergics, and electro-
convulsive therapy produce transient amnesia.
There are two major classes of amnesia
i.e. anterograde amnesia and retrograde
amnesia (Squire et al., 2001).

4.  Retrograde amnesia-is a failure to
retrieve old memories (Markowitsch, 1988; Lucchelli et al., 1997).
Psychogenic amnesia is a kind of retrograde amnesia and it involves
temporary loss of identity as a consequence of strong psychic pressure.
Anterograde and retrograde amnesia usually occur as a consequence of
injury/disease of CNS. Moreover, psychogenic amnesia occurs in
absence of CNS injury. The conversion of short-term memory into long-
term memory involves the gradual transfer of information from
hippocampus system to neocortex. Retrograde amnesia does not affect
short-term memory but it affect short-term memory converted into long-
term memory.

5. Mechanism of Anterograde & Retrograde amnesia
(Role of PAF receptors and Benzodiazepine receptors in Anterograde & Retrograde amnesia)

6. BN52021, a potent membrane PAF receptor antagonist inhibits PAF induced
glutamate release and induction of COX2 gene. BN50730, another potent
intracellular PAF antagonist also found to inhibit COX2 gene induction. MK801, block
NMDA receptors, which inturn inhibits the increase in intracellular Ca2+. NMDA and
Kynurenic acid reversed memory deficits induced by MK801 in mice. BN52021,
BN50730 and MK801, protect the neuronal cells to damage via COX2 and high
concentration of intracellular Ca2+. WEB2170, a PAF antagonist reduced hypoxic
ischaemic brain swelling in the neonatal rat and also causes lack of LTP. Recently
evaluated that PAF antagonist like BN52021 inhibits apoptosis but not necrosis.
Ginkgo biloba extract, containing ginkgolide B (PAF-antagonist), other ginkgolides
and free radical scavengers, has been known to prevent neurodegeneration during
seizures and hypoxia/ischemia may be due to its direct effects on the cholinergic
system. Results of clinical studies of Ginkgo biloba extract (EGB 761) supported its
neuroprotective effect. Microinjection of PAF antagonists into the hippocampus and
amygdala of rats are reported to produce amnesia in step-down inhibitory avoidance
tasks. Synaptosomal and microsomal PAF receptor antagonists BN52021 and
BN50730 respectively, and WEB2086, 2170 are reported to block LTP formation, in
rat hippocampal CA1 in dentate gyrus and in medial vestibular nuclei. It is also
reported that PAF receptor antagonists reduced LTP in the PAF receptor deficient
mice by reducing glutamate induced neurotoxicity and cell death. Therefore, the PAF
is of significance in cell functions as well as in pathological conditions.

7. Platelet activating factor (PAF) antagonists have been reported to impair learning and
memory. Intracerebroventricular injection of PAF attenuates retrograde amnesia
produced by PAF antagonist such as BN52021. Moreover, BN52021 induced amnesia
is also reversed by a non-selective PAF-acetyl-hydrolase (PAF-AH) inhibitor.
Administration of PAF analogue (mc-PAF) into hippocampus (10 min after training),
amygdala (immediately after training), and entorhinal cortex (100 min after training)
has greatly improved retention test performance in habitual task. Administration of
PAF antagonist, BN52021 in the above-mentioned sites and at same time intervals
after training has produced amnesia. Moreover, administration of PAF antagonist
BN52021 into intra-dorsal striatal, region of caudate-putamen, after 2 hours of
training has produced no effect on retention. But administration of mc-PAF and
BN52021 immediately after training has facilitated and impaired the retention
respectively. It suggests the time dependent involvement of PAF in memory process.
The application of BN52021, a PAF antagonist to CA1 region of the hippocampus, has
prevented brief tetanus induced LTP formation. Moreover, PAF antagonists such as
BN52021, BN50370 induced retrograde amnesia, is attenuated by physostigmine
(AchE inhibitor). It may be due to increased concentration of cerebral acetylcholine
and the consequent increase in PAF release.

8. PAF modulates the release of neurotransmitters such as glutamate to facilitate learning
and memory. PAF may act as a retrograde messenger, to induce LTP formation and
PAF analogue has been shown to facilitate process of LTP formation & enhance
learning and memory. PAF analogue (mc-PAF) has greatly improved retention and
PAF antagonist i.e. BN52021 has produced amnesia. PAF antagonists are reported to
produce amnesia in step-down inhibitory avoidance tasks and PAF receptor
antagonists such as BN52021, BN50730, WEB2086 & WEB2170 are reported to
block LTP formation. Intracerebroventricular (i.c.v.) administration of PAF attenuates
retrograde amnesia produced by PAF antagonist such as BN52021. Moreover,
BN52021 induced amnesia is also reversed by a non-selective PAF-acetyl-hydrolase
inhibitor i.e. cigarette smoke extract (CSE). CSE has prevented retrograde amnesia
due to triazolam and brotizolam, where as no such effect has been noted on
anterograde amnesia induced by diazepam, triazolam and brotizolam. Thus retrograde
amnesia observed with triazolam and brotizolam may be mediated through PAF
receptors.

9. The anterograde amnesia produced by alprazolam may be mediated through
benzodiazepines receptors, because it is blocked by a selective benzodiazepines
receptor antagonist such as flumazenil. Moreover, benzodiazepines induced
anterograde amnesia is neither affected by PAF nor by cigarette smoke extract (CSE), a
non-selective PAF-AH inhibitor. It suggests that anterograde amnesia produced by
benzodiazepines is not mediated through PAF receptors. CSE prevent retrograde
amnesia induced by triazolam, brotizolam and BN52021, whereas no such effect was
noted on anterograde amnesia induced by diazepam, triazolam and brotizolam. The
retrograde amnesia observed with BN52021, triazolam and brotizolam may be
mediated through PAF receptors because of PAF-AH inhibitors such as CSE, phenyl
methyl sulfonyl fluoride (PMSF) have prevented their amnesic effect perhaps by
increasing the concentration of PAF. Hence PAF may be an important target site in the
development of retrograde amnesia and play a key role in cognitive processes.