Intranasal Insulin Attenuates the Long-Term Adverse Effects of Neonatal Hyperglycemia on the Hippocampus in Rats.

Hyperglycemia due to relative hypoinsulinism is common in extremely preterm infants and is associated with hippocampus-mediated long-term cognitive impairment. In neonatal rats, hypoinsulinemic hyperglycemia leads to oxidative stress, altered neurochemistry, microgliosis, and abnormal synaptogenesis in the hippocampus. Intranasal insulin (INS) bypasses the blood-brain barrier, targets the brain, and improves synaptogenesis in rodent models, and memory in adult humans with Alzheimer's disease or type 2 diabetes, without altering the blood levels of insulin or glucose. To test whether INS improves hippocampal development in neonatal hyperglycemia, rat pups were subjected to hypoinsulinemic hyperglycemia by injecting streptozotocin (STZ) at a dose of 80 mg/kg i.p. on postnatal day (P) 2 and randomized to INS, 0.3U twice daily from P3-P6 (STZ + INS group), or no treatment (STZ group). The acute effects on hippocampal neurochemical profile and transcript mRNA expression of insulin receptor (Insr), glucose transporters (Glut1, Glut4, and Glut8), and poly(ADP-ribose) polymerase-1 (Parp1, a marker of oxidative stress) were determined on P7 using in vivo 1H MR spectroscopy (MRS) and qPCR. The long-term effects on the neurochemical profile, microgliosis, and synaptogenesis were determined at adulthood using 1H MRS and histochemical analysis. Relative to the control (CONT) group, mean blood glucose concentration was higher from P3 to P6 in the STZ and STZ + INS groups. On P7, MRS showed 10% higher taurine concentration in both STZ groups. qPCR showed 3-folds higher Insr and 5-folds higher Glut8 expression in the two STZ groups. Parp1 expression was 18% higher in the STZ group and normal in the STZ + INS group. At adulthood, blood glucose concentration in the fed state was higher in the STZ and STZ + INS groups. MRS showed 59% higher brain glucose concentration and histochemistry showed microgliosis in the hippocampal subareas in the STZ group. Brain glucose was normal in the STZ + INS group. Compared with the STZ group, phosphocreatine and phosphocreatine/creatine ratio were higher, and microglia in the hippocampal subareas fewer in the STZ + INS group (p < 0.05 for all). Neonatal hyperglycemia was associated with abnormal glucose metabolism and microgliosis in the adult hippocampus. INS administration during hyperglycemia attenuated these adverse effects and improved energy metabolism in the hippocampus.

Losartan Improves Memory, Neurogenesis and Cell Motility in Transgenic Alzheimer's Mice.

Angiotensin receptor blockers (ARBs) have demonstrated multiple neuroprotective benefits in Alzheimer's disease (AD) models. However, their beneficial effects on memory deficits, cholinergic activity, neurogenesis and Amyloid beta (Aß) clearance reveal significant interstudy variability. The delivery route can impact not only delivery but also targeting and therapeutic efficacy of ARBs. Our previous findings on the beneficial effects of intranasally delivered losartan in the APP/PS1 model of AD prompted us to explore the influence of the delivery route by employing here the systemic administration of losartan. Consistent with our previous results with intranasal losartan, repeated intraperitoneal administration (10 mg/kg) resulted in a remarkable decrease in Aß plaques and soluble Aß42, as well as inflammatory cytokines (IL-2, IL-6 and TNFα). The Aß reduction can be ascribed to its facilitated degradation by neprilysin and diminished generation by BACE1. Losartan increased neurogenesis in vivo and in vitro and improved migratory properties of astrocytes isolated from adult transgenic AD mice. In summary, this data together with our previous results suggest therapeutic features of losartan which are independent of delivery route. The improvement of cell motility of Aß-affected astrocytes by losartan deserves further in vivo investigation, which may lead to new strategies for AD treatment.

Intranasal Insulin: a Treatment Strategy for Addiction.

Addiction to substances such as alcohol, cocaine, opioids, and methamphetamine poses a continuing clinical and public challenge globally. Despite progress in understanding substance use disorders, challenges remain in their treatment. Some of these challenges include limited ability of therapeutics to reach the brain (blood-brain barrier), adverse systemic side effects of current medications, and importantly key aspects of addiction not addressed by currently available treatments (such as cognitive impairment). Inability to sustain abstinence or seek treatment due to cognitive deficits such as poor decision-making and impulsivity is known to cause poor treatment outcomes. In this review, we provide an evidenced-based rationale for intranasal drug delivery as a viable and safe treatment modality to bypass the blood-brain barrier and target insulin to the brain to improve the treatment of addiction. Intranasal insulin with improvement of brain cell energy and glucose metabolism, stress hormone reduction, and improved monoamine transmission may be an ideal approach for treating multiple domains of addiction including memory and impulsivity. This may provide additional benefits to enhance current treatment approaches.

Pharmacokinetics in Rat of P8, a Peptide Drug Candidate for the Treatment of Alzheimer's Disease: Stability and Delivery to the Brain.

Strategies to achieve a therapy for Alzheimer's disease (AD) aimed at reducing the effects of amyloid-ß (Aß) have largely involved inhibiting or modifying the activities of the ß- or γ-secretases or by the use of monoclonal antibodies (MAb). We previously offered the potential for a new, early and effective approach for the treatment of AD by a strategy that does not target the secretases. We showed that a family of peptides containing the DEEEDEEL sequence and another independent peptide, all derived from the amino terminus of PS-1, are each capable of markedly reducing the production of Aß in vitro and in mThy1-hAPP transgenic mice. These peptides gave a strong and specific binding with the ectodomain of amyloid-ß protein precursor (AßPP) and did not affect the catalytic activities of ß- or γ-secretase, or the level of AßPP. Critical to the development of any therapeutic for AD is the requirement that it is stable and can be delivered to the brain. We report here data on the metabolic stability and delivery to the rat brain of our lead candidate P8 by intravenous (IV), intranasal (IN), and subcutaneous (SC) administration. Pharmacokinetics (PK) of P8 in rat plasma and CSF following a single dose of P8 demonstrate that SC administration gives better absorption compared to IN and is the delivery method of choice for the further development of P8 as a clinical candidate.

Delivery of Nerve Growth Factor to the Brain via the Olfactory Pathway.

Purpose: To assess the potential of delivering nerve growth factor (NGF) to the brain along the olfactory neural pathway for the treatment of Alzheimer's disease. Methods: Recombinant human NGF (rhNGF) was given as nose drops to anesthetized rats. The rhNGF concentrations in the brain were determined by enzyme-linked immunosorbent assay (ELISA). Results: Following olfactory administration, rhNGF reached the brain within an hour, achieving a concentration of 3400 pM in the olfactory bulb, 660­2200 pM in other brain regions and, 240 pM and 180 pM in the hippocampus and the amygdala, respectively. In contrast, little or no rhNGF was found in the brain following intravenous administration. Conclusions: A significant amount of rhNGF can be delivered to the brain via the olfactory pathway. The detection of rhNGF by ELISA indicates that rhNGF is delivered to the brain relatively intact. The rapid appearance of rhNGF in the brain suggests that it may be transported by an extraneuronal route into the brain via intercellular clefts in the olfactory epithelium. Further work to clarify the transport mechanism is underway. The olfactory pathway is a promising, non-invasive route for drug delivery to the brain, which has potential for the treatment of neurodegenerative diseases including Alzheimer's disease.