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The hypothalamic-pituitary-adrenal axis functions in the maintenance of homeostasis in the various systems of the body. This study was carried out to evaluate the anti-oxidant effect of Azadirachta indica and Spondias mombin on the Hypothalamic-Pituitary- Adrenal axis of zidovudine stress induced wistar rats. 25 adult male wistar rats having an average weight of 180g were used for this study and were divided into 5 groups; group A, group B, group C, group D and group E. Group A is the negative control group that received rat chow and water , group B served as the positive control group that received the administration of 450mg/kg body weight of zidovudine drug, group C received 450mg/kg body weight of zidovudine drug and 500mg/kg body weight of Azadirachta indica, group D received 450mg/kg body weight of zidovudine and 500mg/kg body weight of Spondias mombin leaf extract, while group E received 450mg/kg body weight of zidovudine drug and a combination of 500mg/kg body weight of Azadirachta indica and Spondias mombin. The administration was carried out once a day using orogastric tube for a period of 21 days. At the end of the administration, the rats were sacrificed using chlorofoam inhalation technique, and the whole brain was fixed in 10% neutral buffered formal saline, Blood samples for biochemical estimation were taken. Light microscopic evaluation of the Hypothalamic-Pituitary-Adrenal axis using Haematoxylin and Eosin for group A showed prominent hypothalamic neurons, group B showed degeneration of neurons and presence of vacoules, group C, D,and E showed less vacoules and prominent neurons with lesser vacoules and more prominence of neurons in group C. Haematoxylin and eosin stains for group A, C, and E of the rat pituitary gland, showed prominent acidophilic and basophilic cells with presence of blood vessels, while results of group B and D showed presence of vacoulation with less prominent acidophilic and basophilic cells, Haematoxylin and eosin results for group A showed presence of all the 3 layers of the adrenal cortex and medulla, group B of rat adrenal gland showed presence of haemorrhage in the medulla layer and reticularis, group C had lesser haemorrhage when compared to group D and E. Results of Orange G showed prominence in the acidophilic and basophilic cells in Group A, C, D and E and B showed lesser prominence of orange G stains. Cresoyl Fast Violet stains showed more prominent nissl substance in group A, D, when and E while group B showed a reduction in the expression of nissl stains. Results for stastistical analysis of glutathione peroxidase showed an increase in GPX for group D, when compared to groupA, C and E, and B at (p<0.05), results of Malondialdehyde (MDA) significantly increased in group B (p<0.05) when compared to group A, C, D and E. Hence this study proves that single administration of methanolic leaf extract of Azadirachta indica or Spondias mombin may have neuroprotective potentials and anti-oxidant properties when compared with a combination of the methanolic leaf extract of Azadirachta indica and Spondias mombin leaf extract.