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.