In this third model, perforin forms pores in the plasma membrane of the target cell. Granzymes and perforin are then endocytosed together into large endosomes, and perforin acts on the endosomal membrane to release granzymes into the cytosol. However, the mechanism of how perforin causes release of granzymes from the endosome remains unclear. Perforin is commonly defined as providing cytolytic activity against target cells. Recently new, non-classical, mechanisms have been put forward that perforin can function in non-cytolytic pathways. Perforin has been identified, along with granzyme, as having a noncytolytic role in controlling the reactivation of HSV-1 Carfilzomib neuronal infections without inducing cytotoxicity. Additionally, in mouse model of obesity related insulin resistance and visceral adipose tissue, a lack of perforin showed reduced insulin sensitivity and changed the inflammation status within the VAT lesions, suggesting an immunoregulatory role for perforin in this disease state. Importantly, in this study, the formation of crown like structures, indicative of adipocyte death, was not changed in mice lacking perforin, further emphasizing a noncytolytic role of perforin. Other noncytolytic roles for perforin extend to contributing to CD8 T cell activation during arenavirus infection and regulating antigen presentation of dendritic cells. Previous work, in our lab, shows caspase-3 cleavage is not present until after BBB disruption has already occurred. Given these new roles for perforin and lack of evidence for apoptosis, it is possible that during BBB disruption, perforin is acting in a non-classical mechanism. However, the exact mechanism by which perforin wielding CD8 T cells can induce BBB disruption is yet to be defined. The contribution of molecules delivered by perforin beyond granzyme B also needs to be evaluated. For example, orphan granzymes have recently been proposed to play a role in pathogen clearance and cell-mediated death. Nevertheless, based on the findings put forward in this manuscript, investigating mechanisms of perforin-dependent cytotoxicity are important to the development of novel therapeutic strategies to ameliorate pathology associated with BBB disruption in several devastating neurological disorders. The demonstration that CD8 T cells can serve as a sole source of perforin to induce BBB disruption will greatly aid in this process. Essential medicines are those that satisfy the priority health care needs of a population. They are selected with regard to their public health relevance, evidence on efficacy and safety, and comparative cost-effectiveness. The first global essential medicines list was assembled in 1977 by the World Health Organization, which is revised every other year. Medicines are identified through an evidence-based process in which quality, safety, efficacy and cost-effectiveness are key selection criteria. Although the Model List was not designed as a global standard, it has contributed to global acceptance of the concept of essential medicines and can be used by countries as a guide for the development of their own national essential medicines list. National essential medicines may be helpful in informing decisions in insurance coverage, as they help effective allocation of often limited financial resources, which is important because medicines spending in many countries amounts to about 17% of total health spending or 1.5% of gross domestic product. The WHO’s record of national medicines list has 117 countries, including most of the countries in the Central, East and South Europe.