INTRODUCTION
Cyclooxygenase
(COX) is a prostaglandin G/H synthase (PGHS), which forms prostaglandin
(PG) H2 from
arachidonic
acid (AA), a rate‑limiting enzyme associated with inflammatory
processes. PGH2 is metabolized to physiologically active
PGs, such as PGE2, PGI2,
PGD2, PGF2a, and thromboxane (TX)
A2 [1]. COX-1 and COX-2 are the
isoforms of COX. Different genes translate them with differences in
tissue distribution and biological functions [2].
COX‑1 is constitutively expressed in most cells[3]. In contrast, COX-2 is an inducible enzyme
expressed due to pro‑inflammatory stimuli [4],
associated with inflammation and injury response[5]. However, recent studies indicate a greater
functional significance of COX-2 [6-8]. Compared
with COX-1, the expression of COX-2 is elevated in the glutamatergic
neurons of the hippocampus and cortical regions[9] but not in astrocytes and microglial cells[10]. Thus, COX-2 has a specific role in neurons.
Neuronal COX-2 overexpression is observed in cerebral ischemia,
seizures, brain injury, and neurodegenerative diseases, such as
Parkinson’s, Alzheimer’s, Huntington’s,
etc.[10-14]. These are induced by inflammatory
mediators, excitotoxic, and oxidative[9]. However,
inhibiting COX-2 exacerbates rather than reduces inflammation-related
brain damage [15]. This could lead to AD
progression, elevated COX-2 neuron levels in the early stages[16], and decreased in the late stages[17]. Additionally, cell proliferation and
neuroblast differentiation inside the dentate gyrus are reduced by COX‑2
deficiency because of genetic and pharmacological inhibition[18-20]. Although consolidating spatial memory in
the hippocampus is governed by COX-2 [21, 22], its
role in brain function remains
controversial. This is due to the
significant localization of COX-2 in dendritic spines of neurons and
modifies synapses [23, 24]. However, the
participation mechanisms of COX and PGs in the hippocampal synaptic
plasticity remain unclear.
Therefore, the role of COX‑2 was investigated in the
hippocampal neuron with wild-type
(WT) and COX‑2KO mice. The ability to learn and memorize was
significantly affected by COX-2 gene knockout. This knockout also
decreases the neuronal expression of PSD95, leading to synaptic changes,
and influences gamma wave oscillation through
COX-2/PGE2/cAMP/PKA/CREB/BDNF signaling.