Intranasal Nerve Growth Factor Research Articles

Acute intranasal treatment with nerve growth factor limits the onset of traumatic brain injury in young rats.

Traumatic brain injury (TBI) comprises a primary injury directly induced by impact, which progresses into a secondary injury leading to neuroinflammation, reactive astrogliosis, and cognitive and motor damage. To date, treatment of TBI consists solely of palliative therapies that do not prevent and/or limit the outcomes of secondary damage and only stabilize the deficits. The neurotrophin, nerve growth factor (NGF), delivered to the brain parenchyma following intranasal application, could be a useful means of limiting or improving the outcomes of the secondary injury, as suggested by pre-clinical and clinical data. We evaluated the effect of acute intranasal treatment of young (20-postnatal day) rats, with NGF in a TBI model (weight drop/close head), aggravated by hypoxic complications. Immediately after the trauma, rats were intranasally treated with human recombinant NGF (50 μg·kg-1 ), and motor behavioural test, morphometric and biochemical assays were carried out 24 h later. Acute intranasal NGF prevented the onset of TBI-induced motor disabilities, and decreased reactive astrogliosis, microglial activation and IL-1β content, which after TBI develops to the same extent in the impact zone and the hypothalamus. Intranasal application of NGF was effective in decreasing the motor dysfunction and neuroinflammation in the brain of young rats in our model of TBI. This work forms an initial pre-clinical evaluation of the potential of early intranasal NGF treatment in preventing and limiting the disabling outcomes of TBI, a clinical condition that remains one of the unsolved problems of paediatric neurology.

Intranasal nerve growth factor for prevention and recovery of the outcomes of traumatic brain injury.

Traumatic brain injury is one of the main causes of mortality and disability worldwide. Traumatic brain injury is characterized by a primary injury directly induced by the impact, which progresses into a secondary injury that leads to cellular and metabolic damages, starting in the first few hours and days after primary mechanical injury. To date, traumatic brain injury is not targetable by therapies aimed at preventing and/or limiting the outcomes of secondary damage but only by palliative therapies. Nerve growth factor is a neurotrophin targeting neuronal and non-neuronal cells, potentially useful in preventing/limiting the outcomes of secondary damage in traumatic brain injury. This potential has further increased in the last two decades since the possibility of reaching neurotrophin targets in the brain through its intranasal delivery has been exploited. Indeed, molecules intranasally delivered to the brain parenchyma may easily bypass the blood-brain barrier and reach their therapeutic targets in the brain, with favorable kinetics, dynamics, and safety profile. In the first part of this review, we aimed to report the traumatic brain injury-induced dysfunctional mechanisms that may benefit from nerve growth factor treatment. In the second part, we then exposed the experimental evidence relating to the action of nerve growth factor (both in vitro and in vivo, after administration routes other than intranasal) on some of these mechanisms. In the last part of the work, we, therefore, discussed the few manuscripts that analyze the effects of treatment with nerve growth factor, intranasally delivered to the brain parenchyma, on the outcomes of traumatic brain injury.

Intranasal Delivery of Nerve Growth Factor in Neurodegenerative Diseases and Neurotrauma.

Since the 1980s, the development of a pharmacology based on nerve growth factor (NGF) has been postulated for the therapy of Alzheimer’s disease (AD). This hypothesis was based on the rescuing effect of the neurotrophin on the cholinergic phenotype of the basal forebrain neurons, primarily compromised during the development of AD. Subsequently, the use of NGF was put forward to treat a broader spectrum of neurological conditions affecting the central nervous system, such as Parkinson’s disease, degenerative retinopathies, severe brain traumas and neurodevelopmental dysfunctions. While supported by solid rational assumptions, the progress of a pharmacology founded on these hypotheses has been hampered by the difficulty of conveying NGF towards the brain parenchyma without resorting to invasive and risky delivery methods. At the end of the last century, it was shown that NGF administered intranasally to the olfactory epithelium was able to spread into the brain parenchyma. Notably, after such delivery, pharmacologically relevant concentration of exogenous NGF was found in brain areas located at considerable distances from the injection site along the rostral-caudal axis. These observations paved the way for preclinical characterization and clinical trials on the efficacy of intranasal NGF for the treatment of neurodegenerative diseases and of the consequences of brain trauma. In this review, a summary of the preclinical and clinical studies published to date will be attempted, as well as a discussion about the mechanisms underlying the efficacy and the possible development of the pharmacology based on intranasal conveyance of NGF to the brain.

Topical delivery of nerve growth factor for treatment of ocular and brain disorders

Neurotrophins are a family of proteins that support neuronal proliferation, survival, and differentiation in the central and peripheral nervous systems, and are regulators of neuronal plasticity. Nerve growth factor is one of the best-described neurotrophins and has advanced to clinical trials for treatment of ocular and brain diseases due to its trophic and regenerative properties. Prior trials over the past few decades have produced conflicting results, which have principally been ascribed to adverse effects of systemic nerve growth factor administration, together with poor penetrance of the blood-brain barrier that impairs drug delivery. Contrastingly, recent studies have revealed that topical ocular and intranasal nerve growth factor administration are safe and effective, suggesting that topical nerve growth factor delivery is a potential alternative to both systemic and invasive intracerebral delivery. The therapeutic effects of local nerve growth factor delivery have been extensively investigated for different ophthalmic diseases, including neurotrophic keratitis, glaucoma, retinitis pigmentosa, and dry eye disease. Further, promising pharmacologic effects were reported in an optic glioma model, which indicated that topically administered nerve growth factor diffused far beyond where it was topically applied. These findings support the therapeutic potential of delivering topical nerve growth factor preparations intranasally for acquired and degenerative brain disorders. Preliminary clinical findings in both traumatic and non-traumatic acquired brain injuries are encouraging, especially in pediatric patients, and clinical trials are ongoing. The present review will focus on the therapeutic effects of both ocular and intranasal nerve growth factor delivery for diseases of the brain and eye.

Intranasal nerve growth factor administration improves neurological outcome after GBS meningitis.

Nerve growth factor (NGF) is a neurotrophin that promotes neural recovery and plasticity after experimental brain injury, supporting neuronal growth, differentiation, and survival of brain cells. Only a few studies reported NGF administration in pediatric patients with impaired brain functions after traumatic injuries, ischemic or infectious diseases, such as meningitis. We described the beneficial therapeutic effects of human-recombinant nerve growth factor (hr-NGF) treatment in an infant with persistent unresponsive wakefulness syndrome (UWS), due to late-onset group B Streptococcus meningitis. The infant received five monthly cycles of intranasal hr-NGF (0.1mg/kg, 3 times daily for 7 consecutive days) through a mucosal atomizer device (MAD). NGF administration improved functional [positron emission tomography/computed tomography (PET/CT), single-photon emission/computed tomography (SPECT/CT), and magnetic resonance imaging (MRI)] assessments, electrophysiological [Electroencephalogram (EEG)] studies, as well as main cognitive processes and clinical and neurological functions. After hr-NGF treatment, significant improvements in facial mimicry, attention, motor reactions, oral motility, and feeding capacity were observed. She also recovered some hypothalamic functions and her cough reflex was restored. No side effects were reported during and after the treatment. For the first time ever, hr-NGF has been successfully utilized in an infant with UWS and severe neurologic outcome due to a bacterial meningitis. Although further studies are needed for better understanding the neuroprotective role of this neurotrophin, intranasal hr-NGF administration appears to be a promising and save rescuing strategy treatment in infants with severe neurological impairment after brain damage.

Impact of intranasal application of nerve growth factor on the olfactory epithelium in rats with chemically induced diabetes

ABSTRACTRecent studies suggest that nerve growth factor (NGF) protects olfactory cells and axons from injury in vitro. Eighteen Wistar-Albino rats randomly divided into three groups: control group, diabetic group without NGF, and diabetic with NGF. Intranasal NGF (6 µg/day) was administered over a 5-day period. At the end of 30 days, the olfactory epithelium (OE) of NGF-applied diabetic rats regenerated, the epithelium thickness was significantly higher, and caspase-3 expression was not significantly different from the control. The current results demonstrate that intranasally administered NGF significantly reversed OE morphological changes in diabetes by decreasing diabetes-related cell death and inflammation.

Long-Term Non-Invasive Treatment via Intranasal Administration of Nerve Growth Factor Protects the Human Brain in Frontotemporal Dementia associated with Corticobasal Syndrome: A Pilot Study

Background:Nerve growth factor (NGF) is known for playing a critical protective role on a number of brain neurons in mammals, including humans. NGF can be delivered to the CNS via nasal route and has a neuroprotective action in case of neurodegenerative diseases.Objective:The aim of this study is to investigate for the first time whether purified NGF can play a neuroprotective role on human brain neurons affected by neurodegenerative diseases when administered via nasal route.Methods:Two female patients, both affected by frontotemporal dementia (FTD) associated with corticobasal syndrome (CBS) at different stages of disease progression, received a daily intranasal NGF spray for one year. Clinical/neurological aspects were observed over time. The follow-up study was performed using 18 FDG PET.Results:This case study seems to demonstrate that IN-NGF slows down the common decline caused by FTD/CBS.Conclusions:These findings suggest the potential neuroprotective role of IN-NGF administered in case of neurodegenerative diseases.

Intranasal nerve growth factor attenuating the seizure onset via p75R/Caspase pathway in the experimental epilepsy.

Nerve growth factor (NGF) shows neuroprotection while it is hard to cross the blood-brain barrier due to its large molecular weight. Our study used intranasal delivery of NGF to treat the experimental epilepsy. The seizure was induced by injection of pentylenetetrazol (40mg/kg) into the rat. Based on the behavior performance, the successful models were randomized into control and NGF groups, given medium or NGF intranasally, respectively. The onset and duration of seizure were recorded. The neuron loss was assessed by immunohistochemistry and TUNEL staining. The expressions of Caspase-3, p75R and TrkA were measured by western blotting. Intranasal NGF significantly reduced the seizure onset and shortened the seizure duration. Intranasal NGF alleviated the neuron loss in the epileptic brain. The number of TUNEL-positive cells in the NGF group was less than that in the control group (P<0.05). Overexpression of Caspase-3 and activation of p75R induced by seizure were inhibited by intranasal NGF. Intranasal NGF protected neurons in the epileptic brain by inactivation of p75R/Caspase pathway. Intranasal NGF may be a novel therapeutic strategy for epilepsy.

Combined intranasal nerve growth factor and ventricle neural stem cell grafts prolong survival and improve disease outcome in amyotrophic lateral sclerosis transgenic mice.

Amyotrophic lateral sclerosis (ALS) is a fatal disease that selectively involves motor neurons. Neurotrophic factor supplementation and neural stem cell (NSC) alternative therapy have been used to treat ALS. The two approaches can affect each other in their pathways of action, and there is a possibility for synergism. However, to date, there have been no studies demonstrating the effects of combined therapy in the treatment of ALS. In this study, for the first time, we adopted a method involving the intranasal administration of nerve growth factor combined with lateral ventricle NSC transplantation using G93A-SOD1 transgenic mice as experimental subjects to explore the treatment effect of this combined therapy in ALS. We discover that the combined therapy increase the quantity of TrkA receptors, broaden the migration of exogenous NSCs, further promote active proliferation in neurogenic regions of the brain and enhance the preservation of motor neurons in the spinal cord. Regarding physical activity, the combined therapy improved motor functions, further postponed ALS onset and extended the survival time of the mice.

Intranasal nerve growth factor attenuates tau phosphorylation in brain after traumatic brain injury in rats

Traumatic brain injury (TBI) is a considerable cause of mild cognitive impairment and dementia. Intranasal administration of nerve growth factor (NGF) has previously been found to improve cognitive function after TBI, but the mechanism remains unclear. This study aimed to investigate the effects of intranasal NGF on the tau hyperphosphorylation following TBI. A modified Feeney's weight-drop model was used to induce TBI. Rats were randomly divided into control group, TBI group, TBI+NGF group, TBI+PDTC group and TBI+IL-1ra group. Rats in TBI+NGF group were administered with NGF (5μg/d) for 3d before surgery. Hyperphosphorylated tau protein was remarkable in the peri-contusional cortex area with TBI. Both western blotting and immunostaining results displayed intranasal pretreatment of NGF significantly reduced tau phosphorylation. To evaluate the underlying mechanism, the levels of glycogen synthase kinase 3β (GSK-3β), interleukin-1β (IL-1β), and the DNA binding activity of nuclear factor-κB (NF-κB) were assayed. NGF markedly inhibited GSK-3β. NGF also reduced TBI-induced elevation of IL-1β and NF-κB DNA binding activity. Furthermore, PDTC and IL-1ra were injected to prove a potential signaling pathway among NF-κB, IL-1β and GSK-3β. Taken together, these findings demonstrated that intranasal NGF could effectively attenuate the hyperphosphorylation of tau after TBI, which might involve an integrated signaling pathway related to NF-κB.

Intranasal nerve growth factor bypasses the blood-brain barrier and affects spinal cord neurons in spinal cord injury.

The purpose of this work was to investigate whether, by intranasal administration, the nerve growth factor bypasses the blood-brain barrier and turns over the spinal cord neurons and if such therapeutic approach could be of value in the treatment of spinal cord injury. Adult Sprague-Dawley rats with intact and injured spinal cord received daily intranasal nerve growth factor administration in both nostrils for 1 day or for 3 consecutive weeks. We found an increased content of nerve growth factor and enhanced expression of nerve growth factor receptor in the spinal cord 24 hours after a single intranasal administration of nerve growth factor in healthy rats, while daily treatment for 3 weeks in a model of spinal cord injury improved the deficits in locomotor behaviour and increased spinal content of both nerve growth factor and nerve growth factor receptors. These outcomes suggest that the intranasal nerve growth factor bypasses blood-brain barrier and affects spinal cord neurons in spinal cord injury. They also suggest exploiting the possible therapeutic role of intranasally delivered nerve growth factor for the neuroprotection of damaged spinal nerve cells.

Effect of intranasal NGF administration in injured spinal cord and leptin levels in adult rats

Spinal cord injury alters a number of endogenous biological signals known to be involved in the modulation of neurotrophic and neuroprotective events. Nerve growth factor (NGF) is a neurotrophic factor expressed in neuronal and non-neuronal tissues including spinal cord, and increases after spinal cord injury. Recent findings revealed that leptin, an adipocyte-derived cytokine (adipokine), enhance neuronal survival and exert neuroprotective action, and played an important role in nociceptive behavior induced by nerve injury. Whether NGF affects the expression of leptin in injured spinal cord has not been investigated. The present study was designed to evaluate: (i) whether intranasal NGF administration reached the spinal cord of the rat, (ii) if NGF affects the expression of leptin in the spinal cord and adipose tissue, and (iii) whether intranasal NGF affects the behavioral and spinal cord neuronal deficits induced by spinal cord injury. The result showed that intranasal NGF enhances the expression of (i) NGF and NGF-receptors (TrkA and p75NTR) in injured spinal cord exerting behavioral and neuroprotective action, and (ii) leptin in injured spinal cord and in subcutaneous (white) and interscapular (brown) adipose tissue. Altogether, the present data demonstrate the efficacy of intranasal administration of NGF, and suggest a link between the neurotrophin NGF and the adipokine leptin that may be therapeutically explored in injured spinal cord. Adipobiology 2012; 4: 67-75.

Intranasal delivery of nerve growth factor attenuates aquaporins-4-induced edema following traumatic brain injury in rats

Traumatic brain injury (TBI) remains the leading cause of injury-related death and disability. Brain edema, one of the most major complications of TBI, contributes to elevated intracranial pressure, and poor prognosis following TBI. Nerve growth factor (NGF) appears to be a viable strategy to treat brain edema and TBI. Unfortunately, due to its poor blood-brain barrier (BBB) permeability, the clinical application of NGF has been greatly limited. We previously demonstrated that intranasal NGF could bypass the BBB and distribute throughout the brain. Here we further studied whether intranasal NGF could attenuate TBI-induced brain edema and its putative mechanisms. TBI was produced by a modified weight-drop model. We found that intranasal administration of NGF (5μg/d) attenuated the brain edema, as assayed by hemisphere water content, at 12h, 24h and 72h after TBI induction. This attenuation was associated with a prominent decrease of the content of aquaporin-4, which plays a pivotal role in the formation of brain edema. By the use of RT-PCR and ELISA, we showed that intranasal NGF markedly inhibited the transcription and expression of pro-inflammatory cytokines including IL-1β and TNF-α. An electrophoretic mobility shift assay (EMSA) displayed a significant activation of nuclear factor-κB following TBI, which was, however, much lowered in the NGF-treated rats. Furthermore, upon intranasal NGF supplementation, mitochondria-mediated apoptosis following TBI was minimized, as indicated by upregulation of Bcl-2 and downregulation of caspase-3. Collectively, our findings suggested that intranasal NGF may be a promising strategy to treat brain edema and TBI.

Intranasal nerve growth factor enhances striatal neurogenesis in adult rats with focal cerebral ischemia

Nerve growth factor (NGF) has been proved with the potential of promoting neurogenesis in adult mammalians. This study was aimed to investigate the effect of intranasal (IN) NGF on striatal neurogenesis and functional recovery in adult rats with focal cerebral ischemia. Rats were subjected to middle cerebral artery occlusion (MCAO) for 2 h, and then reperfused. NGF or vehicle was intranasally administered 24 h after cerebral reperfusion, and the treatments continued for 6 consecutive days there after. All animals were injected with 5-bromodeoxyuridine (BrdU) twice daily for 5–7 days after MCAO, and sacrificed 1 day and 28 days, respectively, after the last BrdU injection. Neural cell proliferation and survival in different brain regions were analyzed. Functional tests and immunohistochemical staining were also performed. The results showed that treatment with IN NGF failed to increase cell proliferation but improved survival of newly generated cells in ipsilateral striatum and subventricular zones (SVZ). Double immunofluorescence with BrdU and neuronal nuclei protein, a mature neuronal marker, were increased in striatum and SVZ in rats treated with IN NGF. The functional recovery was also observed at time of neurogenesis enhancement in striate. In conclusion, IN NGF may enhance neurogenesis and survival of newly generated cells, which may result in improved functional recovery after cerebral ischemia.

Intranasal Administration of Nerve Growth Factor Produces Antidepressant-Like Effects in Animals

Many works showed that nerve growth factor (NGF) injected into the brain of animal model emerges potential antidepressant effects. However, this route of administration significantly restricts the application of NGF clinically. Here, we reported that intranasal NGF could provide an alternative to intraventricular injection. The behavioral analysis showed that intranasal administration of NGF reduced the immobility time in forced swimming test (FST) and tail suspension test (TST) in mice. Likewise, intranasal NGF increased the sucrose intake and the locomotor activity in rats after unpredictable chronic mild stress (UCMS). Furthermore, intranasal NGF increased the levels of monoamine neurotransmitters (norepinephrine, dopamine) in the frontal cortex and hippocampus and affected the number of 5-bromodeoxyuridine (BrdU), c-fos and caspase-3 positive neurons in dentate gyrus of hippocampus in rats after UCMS. In summary, intranasal NGF had significant antidepressant effects on animal models of depression and this route of administration may provide a promising way to deliver NGF to brain in a therapeutic perspective.

Combination therapy with intranasal NGF and electroacupuncture enhanced cell proliferation and survival in rats after stroke

Objective: This work was designed to investigate the effects of the combination therapy with intranasal (IN) administration of nerve growth factor (NGF) and electroacupuncture (EA) on neural progenitors and neurological functional recovery in adult rats after focal ischemia.Methods: Rats subjected to 2 hours of middle cerebral artery occlusion (MCAO) were randomly assigned to four groups: Group 1, IN administration of phosphate-buffered saline (PBS) for control; Group 2, IN administration of NGF alone; Group 3, EA with IN administration of PBS; Group 4, IN administration of NGF with EA. Treatments were initiated at 2 hours after MCAO and continued for three consecutive days. All animals received daily injections of 5-bromodeoxyuridine (BrdU) intraperitoneally for 7 days starting at 24 hours after reperfusion and were killed at 2 hours or 21 days after the last BrdU injection. Neurological function and infarct volume were evaluated. Immunohistochemistry for BrdU was performed to identify newborn cells in the ipsilateral subventricular zone and striatum.Results: The combination treatment led to significant improvement in neurological function and reduction in infarct volume. Cell proliferation and survival of progenitors were enhanced in rats treated with the combination treatment.Conclusion: These results suggest that IN administration of NGF and EA may have a synergistic effect in preventing ischemic injury and enhancing functional recovery after focal cerebral ischemia, which may be attributed to enhanced cell proliferation and survival.

The nose may help the brain: intranasal drug delivery for treating neurological diseases

While enormous progress has been made regarding our understanding of the pathogenic mechanisms of neurological diseases, there are only a small number of effective drugs for treating these illnesses. A key obstacle for developing effective drugs for treating neurological diseases is the blockage of drug entrance into the CNS by the BBB [1]. Less than 2% of all small-molecule drugs, and virtually no large-molecule drugs, can cross the BBB. Therefore, it is of critical significance to search for drug-delivery strategies that can effectively deliver drugs into the CNS. An increasing number of studies on both animals and human subjects have suggested that intranasal drug delivery could be used to deliver both smalland largesized drugs into the CNS by bypassing the BBB. It appears increasingly reasonable to conduct clinical trials to determine if intranasal drug delivery may be used to treat neurological diseases. In the 1970s and 1980s there were multiple studies suggesting that intranasal administration may enable substances to directly enter into the brain by pathways involving the olfactory epithelium and olfactory bulb [2]. In 1995 Thorne et al. reported the first quantitative study indicating that intranasal administration could deliver large-sized molecules into the brain by bypassing the BBB [3]. Intranasal administration of wheatgerm agglutinin-horseradish peroxidase (WGA-HRP) led to a significant presence of WGA-HRP in the olfactory bulb of rats, while there was no detectable amount of WGA-HRP in the olfactory bulb after intravenous injection of the same concentration of WGA-HRP. Since 1997, many studies have indicated that intranasal administration can enable large-sized molecules, such as IGF-1, FGF-2, TGF-β1, erythropoietin, IFN-β, HIV-1 Tat, insulin and leptin, to be transported into the CNS at least partially through direct nose-to-brain routes [2,4–9]. A number of studies using animal models of neurological diseases have demonstrated that intranasal delivery of large-sized molecules can produce beneficial effects. For example, intranasal nerve growth factor (NGF) administration can attenuate memory deficits and neurodegeneration in transgenic models of Alzheimer’s disease (AD) [10]; administration of erythropoietin [8] or IGF-I [11] by the intranasal approach can significantly decrease ischemic brain damage; and intranasal delivery of growth factors can also increase neurogenesis in rat brains [9]. We have conducted studies to directly compare the efficacy of intranasal drug delivery with that of intravenous drug delivery in treating brain ischemia. Based on the cell-culture studies showing the protective effects of gallotannin (GT) and nobotanin B – two inhibitors of poly(ADP-ribose) glycohydrolase – against oxidative cell injury [12], we found that intranasal delivery of GT is much more effective than intravenous injection of GT in decreasing ischemic brain injury [13]. On the basis of the in vitro findings that nicotinamide adenine dinucleotide (NAD+) treatment can prevent oxidative stress-induced cell death [14], we also found that intranasal NAD+ administration can produce up to 90% decreases in infarct formation when given 2 h after ischemia, which is the most profound protection ever reported from drugs that have been administered hours after ischemic onset [15,16].

S3-04-03: Bypassing the blood-brain barrier with intranasal delivery to treat Alzheimer’s disease and related disorders

not available. S3-04-02 NGF GENE THERAPY Mark H. Tuszynski, Leon Thal, Mary Pay, Gang Tong, Hoi-Sang U, Roy Bakay, Steve Potkin, Gilbert Ho, Raymond Bartus, Zoe Arvanitakis, David Bennett, David Salmon, University of California San Diego and VA Medical Center, La Jolla, CA, USA; University of California, San Diego, La Jolla, CA, USA; Rush University Medical Center, Chicago, IL, USA; University of California, Irvine, Irvine, CA, USA; Ceregene, Inc., San Diego, CA, USA. Contact e-mail: mtuszynski@ucsd.edu Background: Cholinergic neuron loss is a cardinal feature of Alzheimer disease (AD). Nerve Growth Factor (NGF) stimulates cholinergic function, improves memory and prevents cholinergic degeneration in animal models of injury, amyloid overexpression and aging. Objective: We performed a Phase 1 trial of ex vivo NGF gene delivery in eight mild AD patients to assess safety and feasibility. Methods: Autologous fibroblasts genetically modified to express human NGF were injected into the basal forebrain to act as long-term sources of growth factor production. Adverse effect profile, cognitive function and PET scans were serially monitored. Results: Two sedated but non-anesthetized subjects moved as cells were intracerebrally injected, causing bleeds; all subsequent injections performed under anesthesia were without complication. After follow-up of up to 4 years post-treatment, no long-term adverse effects of NGF have occurred. Evaluation of the MMSE and ADAS-Cog suggested that the rate of cognitive decline post-treatment was reduced approximately 50%, over a mean period of two years. Serial PET scans demonstrated significant increases in cortical 18-fluorodeoxyglucose after treatment. Brain autopsy from one subject demonstrated robust growth responses to NGF. Conclusions: Additional clinical trials of NGF for AD are warranted. A Phase 1 trial of AAV-NGF gene delivery is in progress, and Phase 2 trials are planned. S3-04-03 BYPASSING THE BLOOD-BRAIN BARRIER WITH INTRANASAL DELIVERY TO TREAT ALZHEIMER’S DISEASE AND RELATED DISORDERS William H. Frey II, Alzheimer’s Research Center, Regions Hospital, St Paul, MN, USA. Contact e-mail: Alzheimr@umn.edu Background: Intranasal delivery provides a practical, noninvasive, method of bypassing the blood-brain barrier to deliver therapeutic agents to the brain and spinal cord. [See Dhanda (2005) Drug Delivery Technology 5(4):64-72 for a review.] Objective(s): Intranasal delivery allows drugs that do not cross the blood-brain barrier to be delivered to the central nervous system (CNS) within minutes. It also directly targets drugs that do cross the blood-brain barrier to the CNS, eliminating the need for systemic delivery and thereby reducing unwanted systemic side effects. Methods: Intranasal delivery does not require any modification of the therapeutic agent. A wide variety of therapeutics, including both small molecules and macromolecules are rapidly delivered intranasally to the brain and can target the olfactory and connected memory areas affected by Alzheimer’s disease (AD). This is possible because of the unique connection that the olfactory and trigeminal nerves provide between the brain and external environment [Thorne (2004) Neuroscience 127:481-496]. Conclusions: Using the intranasal delivery method, which I first introduced in 1989, researchers in Italy have reversed neurodegeneration and rescued memory in a transgenic mouse model of AD [Capsoni (2002) PNAS 99(19):1243212437 and De Rosa (2005) PNAS 102(10): 3811-3816]. We and others have demonstrated both treatment of and protection against stroke in animals with intranasal IGF-I [Liu (2004) Journal of Stroke and Cerebrovascular Diseases 13(1): 16-23], deferoxamine [Panter (2005) Society for Neuroscience Abstracts #669.5] and EPO [Yu (2005) Neurosci Lett 387:5]. Researchers in Israel have used intranasal delivery to target NAP and ADNF to the brain to treat anxiety and neurodegeneration [Alcalay (2004) Neuroscience Letters 361:128-131; Gozes (2000) JPET 293(3):10911098.] Intranasal NGF and EGF have been shown to stimulate neurogenesis in adult animals [Jin (2003) Ann Neurol 53:405-409]. Our collaborators [Reger (2006) Neurobiology of Aging: in press] have demonstrated that intranasal insulin acutely improves memory in patients with AD and those with mild cognitive impairment while researchers in Germany [Benedict (2004) Psychoneuroimmunol. 29:1326-1334] have shown that eight weeks of intranasal insulin treatment improves both memory and mood in normal adult humans. This new method of delivery can revolutionize the treatment of Alzheimer’s disease, stroke, and other brain disorders. S3-04-04 IMMUNOTHERAPY Roger Nitsch, University of Zurich, Zurich, Switzerland. Contact e-mail: nitsch@bli.unizh.ch Abstract not available.not available. S3-04-05 PHAGE THERAPY IN ALZHEIMER’S DISEASE Beka Solomon, Tel-Aviv Univ, Ramat Aviv, Israel. Contact e-mail: