Background：
With the spread of HIV-1 infection and the availability of antiretroviral therapy, HIV-associated neurocognitive disorder (HAND) has become the most prevalent neurological complication in 39 million HIV-infected patients worldwide. The pathology of HAND is characterized by microglia activation, widespread reactive astrocytosis, inflammatory damage due to infiltration of multinucleated macrophages and monocytes, and neuronal damage. HAND patients exhibit characteristic deficits in neuronal networks and dendritic spines caused by inflammation, which are necessary for learning and memory. In this study, HIV-1 gp120 tg mice, which highly express HIV-1 LAV gp120 (X4) protein in astrocytes, were used as an alternative model of HAND. In our group's previous study, 12-month-old gp120 mice exhibited significant cognitive, spatial learning, and memory deficits compared to WT group mice. Kynurenine acid (KYNA), an endogenous metabolite of astrocyte KP (kynurenine pathway), is a well-recognized neuroprotective agent and is widely used in the treatment of neurodegenerative diseases. Because peripheral KYNA is unable to cross the blood-brain barrier, we intraperitoneally injected gp120 tg mice with the KYNA precursor kynurenine (KYN) and probenecid (PROB), which inhibits KYNA loss.
Methods：
All mice were divided into 2 groups: gp120 tg + PBS, gp120 tg + KYN and PROB. Mice were injected intraperitoneally with KYN (400 mg/kg) and PROB (200 mg/kg) every two days for 14 days. Morris water maze test was carried out on the 5th day of injection. Concealed platform test: For the first five days, mice were trained to find the platform hidden under the surface of the water from random locations in the four quadrants, and the swimming trajectory and latency of the mice were recorded each time. Spatial exploration test: on day 7, after the hidden platform was withdrawn, the mice were released from random locations, and the mice's 60 s swimming trajectories were recorded. The open field test was carried out on day 14 of injection. At the beginning of the test, the mice were sequentially released to the central area of the open field device, and the mice were allowed to move freely in the open field device. Their behavior and movement trajectories were recorded for 15 min. At the end of the monitoring time, the mice were removed from the open field device and the feces and urine excreted by the mice were cleaned up. The mice were anesthetized on day 15, and the brains were removed after cardiac perfusion.
Results：
After two weeks of continuous treatment, the results of Morris water maze analysis showed that intraperitoneal injection of KYN and PROB significantly improved spatial learning and memory deficits in 12-month-old gp120 tg mice (p<0.001). The results of the open field test showed that after intraperitoneal injection of KYN and PROB, 12-month-old gp120 tg mice had a greatly enhanced desire to explore the center area of the open field and their nervousness during exploration was significantly improved (p<0.001). The results of Nissl staining showed that 12-month-old gp120 tg mice hippocampal areas had fewer Nissl vesicles, significantly more vacuoles, larger cell-surrounding gaps, and a generalized inflammatory cell infiltration. After injection of KYN and PROB, the number of neurons in the gp120 tg mice hippocampal area remained at normal levels, with a mild reduction in cell volume and slight inflammatory cell infiltration.
Conclusion：
KYN/KYNA ameliorated cognitive deficits and neuropathologic deficits in gp120 tg mice via blood-brain barrier. These findings provide new evidence for the treatment of HAND with KYNA. (Acknowledgements: This study was supported by National Natural Science Foundation of China, No. 82172259 to H. Cao and Grant from School of Public Health of Southern Medical University, China, Grant No. GW202329 to H. Cao; Corresponding author: Hong Cao, gzhcao@smu.edu.cn)
No relevant conflicts of interest to declare.
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