Abstract
Parenteral use of drugs; such as opiates exert immunomodulatory effects and serve as a cofactor in the progression of HIV-1 infection, thereby potentiating HIV related neurotoxicity ultimately leading to progression of NeuroAIDS. Morphine exposure is known to induce apoptosis, down regulate cAMP response element-binding (CREB) expression and decrease in dendritic branching and spine density in cultured cells. Use of neuroprotective agent; brain derived neurotropic factor (BDNF), which protects neurons against these effects, could be of therapeutic benefit in the treatment of opiate addiction. Previous studies have shown that BDNF was not transported through the blood brain barrier (BBB) in-vivo.; and hence it is not effective in-vivo. Therefore development of a drug delivery system that can cross BBB may have significant therapeutic advantage. In the present study, we hypothesized that magnetically guided nanocarrier may provide a viable approach for targeting BDNF across the BBB. We developed a magnetic nanoparticle (MNP) based carrier bound to BDNF and evaluated its efficacy and ability to transmigrate across the BBB using an in-vitro BBB model. The end point determinations of BDNF that crossed BBB were apoptosis, CREB expression and dendritic spine density measurement. We found that transmigrated BDNF was effective in suppressing the morphine induced apoptosis, inducing CREB expression and restoring the spine density. Our results suggest that the developed nanocarrier will provide a potential therapeutic approach to treat opiate addiction, protect neurotoxicity and synaptic density degeneration.
Highlights
Drug abuse is one of the major concerns of present United States
Efficiency of brain derived neurotropic factor (BDNF) binding to magnetic nanoparticle (MNP) was calculated by using different ratios of MNP and BDNF (1:0.05, 1:0.01, 1:0.015, 1:0.02, 1:0.025, 1:0.03, 1:0.35) in TE buffer
Data given on figure 2 represents the binding isotherm of BDNF binding to MNP
Summary
Drug abuse is one of the major concerns of present United States. Drugs of abuse such as opiates, cocaine, methamphetamine are frequently being used by individuals infected with HIV-1 [1]. HIV and most abused drugs (morphine, heroine, etc) target areas in brain such as basal ganglia and cortex that are rich in opioidergic receptors [4]. Especially morphine and heroin are known to exert their effects through m-opiate receptor, the exact mechanism by which opiates act as a cofactor for HIV infection is not clear. Opiates have been shown to induce apoptosis of neuronal cells, microgila, macrophages and monocytes. The need to protect neuronal cells against the toxic effect of drugs of abuse using neuroprotective agents is of therapeutic importance
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