Delivery of macromolecular drugs to the brain is impeded by the blood brain barrier. The recruitment of leukocytes to lesions in the brain, a typical feature of neuroinflammation response which occurs in cerebral ischemia, offers a unique opportunity to deliver drugs to inflammation sites in the brain. In the present study, cross-linked dendrigraft poly-L-lysine (DGL) nanoparticles containing cis-aconitic anhydride-modified catalase and modified with PGP, an endogenous tripeptide that acts as a ligand with high affinity to neutrophils, were developed to form the cl PGP-PEG-DGL/CAT-Aco system. Significant binding efficiency to neutrophils, efficient protection of catalase enzymatic activity from degradation and effective transport to receiver cells were revealed in the delivery system. Delivery of catalase to ischemic subregions and cerebral neurocytes in MCAO mice was significantly enhanced, which obviously reducing infarct volume in MCAO mice. Thus, the therapeutic outcome of cerebral ischemia was greatly improved. The underlying mechanism was found to be related to the inhibition of ROS-mediated apoptosis. Considering that neuroinflammation occurs in many neurological disorders, the strategy developed here is not only promising for treatment of cerebral ischemia but also an effective approach for various CNS diseases related to inflammation.

A molecular Trojan horse carrying drugs for cerebral ischemic stroke has the potential to alleviate injuries.

Exploiting cells as vehicles combined with nanoparticles combined with therapy has attracted increasing attention in the world recently. Red blood cells, leukocytes and stem cells have been used for tumor immunotherapy, tissue regeneration and inflammatory disorders, and it is known that neutrophils can accumulate in brain lesions in many brain diseases including depression. N-Acetyl Pro-Gly-Pro (PGP) peptide shows high specific binding affinity to neutrophils through the CXCR2 receptor. In this study, PGP was used to modify baicalein-loaded solid lipid nanoparticles (PGP-SLNs) to facilitate binding to neutrophils in vivo. Brain-targeted delivery to the basolateral amygdala (BLA) was demonstrated by enhanced concentration of baicalein in the BLA. An enhanced anti-depressant effect was observed in vitro and in vivo. The mechanism involved inhibition of apoptosis and a decrease in lactate dehydrogenase release. Behavioral evaluation carried out with rats demonstrated that anti-depression outcomes were achieved. The results indicate that PGP-SLNs decrease immobility time, increase swimming time and climbing time and attenuate locomotion in olfactory-bulbectomized (OB) rats. In conclusion, PGP modification is a strategy for targeting the brain with a cell-nanoparticle delivery system for depression therapy.

Strong evidence has shown that caffeine exerts antidepressant-like effects in chronic stress situations by increasing dopamine levels.

Ketamine is a popular recreational substance of abuse that induces persistent behavioral deficits. Although disrupted oxytocinergic systems have been considered to modulate vulnerability to developing drugs of abuse, the involvement of central oxytocin in behavioral abnormalities caused by chronic ketamine has remained largely unknown. Herein, we aimed to investigate the potential role of oxytocin in the medial prefrontal cortex (mPFC) in social avoidance and cognitive impairment resulting from repeated ketamine administration in mice. We found that ketamine injection (5 mg/kg, i.p.) for 10 days followed by a 6-day withdrawal period induced behavioral disturbances in social interaction and cognitive performance, as well as reduced oxytocin levels both at the periphery and in the mPFC. Repeated ketamine exposure also inhibited mPFC neuronal activity as measured by a decrease in c-fos-positive cells. Furthermore, direct microinjection of oxytocin into the mPFC reversed the social avoidance and cognitive impairment following chronic ketamine exposure. In addition, oxytocin administration normalized ketamine-induced inflammatory cytokines including TNF-α, IL-6, and IL-1β levels. Moreover, the activation of immune markers such as neutrophils and monocytes, by ketamine was restored in oxytocin-treated mice. Finally, the reversal effects of oxytocin on behavioral performance were blocked by pre-infusion of the oxytocin receptor antagonist atosiban into the mPFC. These results demonstrate that enhancing oxytocin signaling in the mPFC is a potential pathway to reverse social avoidance and cognitive impairment caused by ketamine, partly through inhibition of inflammatory stimulation.