Cypermethrin (CYP) is a synthetic pyrethroid. It crosses the blood-brain barrier in pests and creates neurotoxicity in the
CNS. Hydroxytyrosol (HT) is considered a powerful natural antioxidant, it is found in olive leaf, olive pulp and olive oil.
Hydroxytyrosol is the only phenol that is capable to pass the blood-brain barrier and permits it to involve free radicals
throughout the CNS. We designed this study to explore the possible protective role of HT against the neurotoxic effect induced
by CYP. Thirty male adult albino rats were divided into three groups. Control group; subdivided into: control, corn oil, HT
groups, CYP treated and CYP, CYP+ HT treated group. Treatments were given by gavage for 14 days. The cerebrum tissue
was prepared for histopathological examination and immunohistochemical detection of caspase 3 and GFAP. We also assessed
the level of GAPA and ACH in the tissue and the oxidative enzymatic and the lipid perioxidation profile. We observed that
the concomitant use of HT with the CYP diminished the signs of hyper excitability induced by the CYP which confirmed by
significant decrease in the level of GABA in cerebrum tissue. HT counteracted the histopathological changes induced by CYP
and significantly downregulate the caspase -3 and GFAP expression in cerebrum tissue. A rescue of the oxidative enzymatic
activity, lipid peroxidation profiles was also evident in the CYP+HT-treated group. We concluded that HT exhibited substantial
antioxidant and anti-apoptotic impacts on the cerebral cortex cytomorphological alterations and apoptosis produced by CYP
in cerebrum tissue.