D description in the CPP internalization mechanisms, as well as other properties including stability, toxicity and immunogenicity had been reviewed elsewhere [199]. Here we focus on use of CPPs for delivery of proteins to CNS. Schwarze and colleagues published a seminal work demonstrating potential of CPP to deliver proteins across BBB [200]. In their study the NH2-terminal TAT (477)-galactosidase fusion protein (120 kDa) injected i.p. in mice was detected by immunochemical staining initially at 2 hr in brain microvessels and after that at 4 hr in brain parenchyma. No PK studies were performed. Nonetheless galactosidase activity was visualized in sagittal and coronal brain sections as well as in liver, kidney, lung and heart (myocardium) and spleen. TAT didn’t seem to disrupt BBB as the Evan’s blue albumin complexes co-injected with TAT had been excluded in the brain tissues. Subsequently, TAT peptide was fused with GDNF and injected i.p. in a mouse model of PD. The fusion protein crossed the BBB and reached substantia nigra as was shown by immunohistochemical staining. Nonetheless, the therapy didn’t stop the loss of dopaminergic neurons in PD mice, possibly since the quantity of the fusion protein delivered to the target internet site was not enough [201]. A TAT-based technique was also employed to deliver Bcl-xL protein, a well-characterized death-suppression molecule, towards the CNS for treatment of stroke. Intraperitoneal injection of TAT and Bcl-xL fusion protein resulted in a robust protein transduction in neurons, and also a dose-dependent decrease of cerebral infarction inside a mouse middle cerebral artery occlusion (MCAO) model of ischemic stroke [202]. Similarly, a decreased infarct volume and neurological deficits have been observed soon after i.v. injection of TAT-Bcl-xL fusion protein 1 hr. before or quickly just after the ischemia induced within a rat MCAO model [203]. A current study reported that TAT-leptin fusion protein was i.v. injected to mice fed with high-fat eating plan. Immunohistochemical stainingNIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptJ Control Release. Author manuscript; offered in PMC 2015 September 28.Yi et al.Pagesuggested increase in leptin accumulation in hypothalamus inside the TAT-leptin treated mice, when compared with the unmodified leptin or saline-treated animals. Importantly, TAT-leptin also prevented body-weight obtain much more effectively when compared with leptin [204]. Cai et al. lately described constructive effects of TAT-mediated delivery of neuroglobin (Ngb) on focal cerebral ischemia outcome in mice [205]. After i.v. injection the SSTR2 manufacturer TAT-Ngb fusion protein was detected in mice brain tissues by immunohistochemistry and western blotting. The group treated with TAT-Ngb 2 hr. ahead of MCAO showed smaller sized brain infarct volume and enhanced neurologic outcomes when compared with the handle groups. Additionally, the group treated with TAT-Ngb PI3Kγ custom synthesis following MCAO and reperfusion showed considerably improved neuronal survival in the striatum, in comparison to the controls [205]. In addition to TAT some other CPPs, for instance Syn-B vectors and Rabies virus glycoproteinderived peptide (RDP), have been also shown to provide modest molecules and proteins across BBB [206, 207]. For example, Xiang et al reported efficient hippocampus targeting by a galactosidase-RDP fusion protein [206]. Interestingly, a easy mixing of a protein with CPP also enhanced delivery of a number of proteins for instance -galactosidase, human IgG and IgM to mouse brain [208]. However, CPP have displayed a variety of toxicities includin.