Nanowired-drug delivery enhances neuroprotective efficacy of compounds and reduces spinal cord edema formation and improves functional outcome following spinal cord injury in the rat.

The possibility that drugs attached to nanowires enhance their therapeutic efficacy was examined in a rat model of spinal cord injury (SCI). Three Acure compounds AP-173, AP-713 and AP-364 were tagged with TiO(2)-based nanowires (50-60 nm) and applied over the traumatized cord either 5 or 60 min after SCI in rats produced by a longitudinal incision into the right dorsal horn of the T10-11 segments under equithesin anaesthesia. Normal compounds were used for comparison. After 5 h SCI, behavioral outcome, blood-spinal cord barrier (BSCB) permeability, edema formation and cell injury were examined. Topical application of nanowired compound AP-713 (10 microg in 20 microL) when applied either 5 or 60 min after injury markedly attenuated behavioral dysfunction at 2-3 h after SCI and reduces BSCB disruption, edema formation and cord pathology at 5 h compared to other compounds. Whereas normal compounds applied at 5 min after injury (but not after 60 min) had some significant but less beneficial effects compared to their nanowired combinations. On the other hand, nanowires alone did not influence spinal cord pathology or motor function after SCI. Taken together, our results indicate that the nanowired-drug-delivery enhances the neuroprotective efficacy of drugs in SCI and reduces functional outcome compared to normal compounds even applied at a later stage following trauma, not reported earlier.

Nano-drug delivery and neuroprotection in spinal cord injury.

Recently nano-drug delivery to the central nervous system (CNS) has been shown to be more effective than the parent compound by itself. An increased availability of the drug for longer periods to the brain or spinal cord and/or a decrease in the drug metabolism altogether could lead to potentiation of the pharmacological activity of the nano-delivered compounds. However, it is still unclear whether the nanocarriers used to deliver the drugs may itself has any potential neurotoxic activity. Although, nanodrug-delivery appears to be a quite promising therapeutic tool for the future clinical therapy, its advantages and limitations for the routine use of patients still needs to be elucidated. Our laboratory is engaged to study a plethora of potential neuroprotective novel compounds delivered to the CNS using nanowiring techniques following brain or spinal cord trauma. Our investigations show that nanowired drugs, if delivered locally following spinal cord injury achieve better neuroprotection than the parent compounds. This effect of nano-drug delivery appears to be very selective in nature. Thus, a clear differentiation based on the compounds used for nano-drug delivery can be seen on various pathological parameters in spinal cord injury. These observations suggest that nanowiring may itself do not induce neuroprotection, but enhance the neuroprotective ability of compounds after trauma. This review describes some recent advances in nano-drug delivery to the CNS in relation to novel neuroprotective strategies with special emphasis on spinal cord trauma based on our own observations and recent findings from our laboratory investigations.

Probiotic modulation of symbiotic gut microbial-host metabolic interactions in a humanized microbiome mouse model.

The transgenomic metabolic effects of exposure to either Lactobacillus paracasei or Lactobacillus rhamnosus probiotics have been measured and mapped in humanized extended genome mice (germ-free mice colonized with human baby flora). Statistical analysis of the compartmental fluctuations in diverse metabolic compartments, including biofluids, tissue and cecal short-chain fatty acids (SCFAs) in relation to microbial population modulation generated a novel top-down systems biology view of the host response to probiotic intervention. Probiotic exposure exerted microbiome modification and resulted in altered hepatic lipid metabolism coupled with lowered plasma lipoprotein levels and apparent stimulated glycolysis. Probiotic treatments also altered a diverse range of pathways outcomes, including amino-acid metabolism, methylamines and SCFAs. The novel application of hierarchical-principal component analysis allowed visualization of multicompartmental transgenomic metabolic interactions that could also be resolved at the compartment and pathway level. These integrated system investigations demonstrate the potential of metabolic profiling as a top-down systems biology driver for investigating the mechanistic basis of probiotic action and the therapeutic surveillance of the gut microbial activity related to dietary supplementation of probiotics.

Drug delivery to the spinal cord tagged with nanowire enhances neuroprotective efficacy and functional recovery following trauma to the rat spinal cord.

The possibility that drugs attached to innocuous nanowires enhance their delivery within the central nervous system (CNS) and thereby increase their therapeutic efficacy was examined in a rat model of spinal cord injury (SCI). Three compounds--AP173 (SCI-1), AP713 (SCI-2), and AP364 (SCI-5) (Acure Pharma, Uppsala, Sweden)--were tagged with TiO(2)-based nanowires using standard procedure. Normal compounds were used for comparison. SCI was produced by making a longitudinal incision into the right dorsal horn of the T10-T11 segments under Equithesin anesthesia. The compounds, either alone or tagged with nanowires, were applied topically within 5 to 10 min after SCI. In these rats, behavioral outcome, blood-spinal cord barrier (BSCB) permeability, edema formation, and cell injury were examined at 5 h after injury. Topical application of normal compounds in high quantity (10 microg in 20 microL) attenuated behavioral dysfunction (3 h after trauma), edema formation, and cell injury, as well as reducing BSCB permeability to Evans blue albumin and (131)I. These beneficial effects are most pronounced with AP713 (SCI-2) treatment. Interestingly, when these compounds were administered in identical conditions after tagging with nanowires, their beneficial effects on functional recovery and spinal cord pathology were further enhanced. However, topical administration of nanowires alone did not influence trauma-induced spinal cord pathology or motor functions. Taken together, our results, probably for the first time, indicate that drug delivery and therapeutic efficacy are enhanced when the compounds are administered with nanowires.

A potent serotonin-modulating compound AP-267 attenuates morphine withdrawal-induced blood-brain barrier dysfunction in rats.

The possibility that a serotonin 5-HT2c receptor-modulating compound, AP-267, will influence spontaneous morphine withdrawal symptoms and the alterations in the brain fluid microenvironment was examined in a rat model. Daily administration of morphine (10 mg/kg, i.p.) for 10 days resulted in dependence of rats as seen by loss of analgesic response. On the 11th day, no morphine administration was given. This resulted in profound withdrawal symptoms 24 h after morphine withdrawal. The magnitude and severity of these symptoms were increased further 48 h after withdrawal. Measurement of the blood-brain barrier (BBB) permeability, a measure of perturbed brain fluid microenvironment showed leakage of Evans blue and radioiodine tracers in several parts of the brain in rats showing withdrawal symptoms. Whereas, rats treated with AP-267 either on the 1st day or 2nd day morphine withdrawal showed much less symptoms and leakage of the BBB. Taken together, these observations suggest that (a) stress associated with the withdrawal symptoms are sufficient enough to induce breakdown of the BBB function, and (b) modulation of serotonin 5-HT2c receptors may have some protective influence on the stress symptoms and the BBB disruption.