Neuroscience Research

ALZET Research Alert - June 2014

ALZET Research Alert: Neuroscience ResearchThe blood-brain barrier (BBB) presents an impediment for effective delivery of agents to the central nervous system (CNS). For nearly 4 decades, ALZET® Osmotic Pumps have been used as a reliable and convenient tool to overcome the BBB and deliver agents directly to their site of action. These small, implantable pumps deliver a precise and continuous dose, without interference in elaborate behavioral testing, and without the stress associated with other methods requiring frequent animal handling. ALZET pumps are now an integral component in neuroscience research, as evidenced by the thousands of publications describing their use in studies on spinal cord injury, neurodegeneration, depression, brain cancer, and more. Read on for relevant research in these areas. Contact ALZET Technical Services for more information at 800.692.2990 or alzet@durect.com.

microRNA-155 inhibition prolongs survival in ALS mice
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease - with few treatment options - characterized by the selective loss of motor neurons in the brain and spinal cord. Koval et al. evaluated the therapeutic potential of novel microRNA inhibitors (anti-miR-155) in the superoxide dismutase 1 (SOD1) mouse model of ALS. Since these agents don’t cross the BBB, ALZET pumps (Models 2004 and 2006) were used to enable direct intraventricular (ICV) delivery for 28 or 42 days. Continuous infusion of anti-miR-155 resulted in widespread functional distribution in the brain and spinal cord. SOD1 mice treated with anti-miR-155 survived 10 days longer than those treated with scrambled control anti-miR. The researchers concluded that miR-155 is a promising therapeutic target for ALS and other neurological disorders.
Human Molecular Genetics 2013;22(20):4127-4135

Preclinical immunotoxin therapy for brain tumors
The EGF receptor gene (EGFR), and its deletion mutant, EGFRvIII, are frequently overexpressed in glioblastoma. Chandramohan et al. tested the preclinical efficacy of D2C7-(scdsFv)-PE38KDE, a recombinant immunotoxin reactive with the 55-amino acid region of the extracellular domain of EGFRwt and EGFRvIII. Following continuous, intracranial infusion of the immunotoxin for 3 and 7 days in NSG mice, Chandramohan observed “significant increase in survival at a very low dose…” ALZET pumps enabled the researchers to achieve high local concentration and homogenous distribution of the immunotoxin at the tumor site, strategies shown to be effective in the treatment of glioblastoma. The study suggests that this immunotoxin displays significant potential for treating brain tumors expressing either EGFRwt, EFGRvIII, or both.
Clinical Cancer Research 2013;19(17):4717-27

Enzyme replacement therapy by IT infusion repairs CNS defects
Mucopolysaccharidosis type II (MPS II), or Hunter syndrome, is a rare CNS disorder caused by a deficiency in iduronate-2-sulfatase (IDS), an enzyme involved in glycosaminoglycan (GAG) degradation. Sohn et al. evaluated the efficacy of enzyme replacement therapy (ERT) by continuous, intrathecal (IT) infusion in the IDS knock-out mouse model for MPS II. MPSII mice were treated with increasing doses of recombinant human IDS (rh-IDS) for 3 weeks using ALZET pumps (Model 2004), which were used to overcome the BBB and enable slow, continuous delivery to the CSF. Results showed that CNS defects were repaired in mice treated at the highest rh-IDS dose (12 µg/day). Brain tissues from these animals showed decreased GAG concentrations, reduced vacuolation and restored anti-NeuN signaling, which represents intact neurons. Sohn proposed continuous IT infusion of rh-IDS as a potential therapeutic method for treating neurological deterioration in patients with MPS II.
Am J Med Gen Part A 2013; 161A:1036-1043

ATP modulates depression in mice
Studies by Cao et al. indicate that astrocyte-derived ATP plays a key role in the underlying biology of major depressive disorder. Mice that were susceptible to depressive behaviors were found to have low levels of ATP in their brains. Continuous ICV infusion of ATP using ALZET pumps (Model 1007D) induced dramatic antidepressant-like effects in these mice during a 7-day treatment period. Blockage of ATP release from astrocytes also caused depressive-like behaviors that could be relieved by ATP administration. Similarly, stimulation of endogenous ATP release from astrocytes induced antidepressant-like effects in mice. These results confirm the involvement of astrocytic ATP in the biological mechanism of depression.
Nature Med 2013;19(6):773-777

Anti-tau infusion improves tau pathology
Tau aggregation is a pathological hallmark in neurodegenerative diseases grouped as tauopathies, which include Alzheimer’s. Yanamandra et al. evaluated the therapeutic efficacy of monoclonal antibodies designed to block trans-cellular propagation of tau aggregates, a process directly associated with the progression of tau pathology. ALZET pumps (Model 2006) were used for chronic ICV delivery of three different anti-tau antibodies in P301S human tau transgenic mice. ALZET pump infusion resulted in high antibody concentrations in CSF and serum. After the 3 month treatment period, all three antibodies effectively blocked the development of tau seeding activity detected in brain lysates. They also reduced microglial activation, and improved cognitive deficits in diseased mice. Thus tauopathies could be effectively treated with immunotherapy designed to block trans-cellular tau propagation.
Neuron 2013;80:402-414

IL-12/23 p40 inhibition improves cognitive deficits
Progressive inflammatory processes in the CNS are believed to contribute to the pathogenesis of age-related diseases, including Alzheimer’s disease (AD). Tan et al. used the senescence-accelerated mouse prone-8 (SAMP8) model to study the effect of IL-12/23 p40 subunit signal blocking on AD pathology. ALZET pumps (Model 1004) and ALZET Brain Infusion Kit 3 were used for ICV infusion of p40 siRNA, or p40-specific antibody for 4 weeks. Results show overall cognitive improvements following knock down of brain p40 subunit in SAMP8 mice. According to Tan “this approach of pump mediated p40 siRNA infusion is efficient in down-regulation of p40 mRNA (by 60%) and protein (by 49%) levels…” Efficient and stable knockdown of gene expression was attributed to “constant minipump-mediated infusion into the ventricle”. Tan et al. concluded that p40 inhibition represents a promising therapeutic option for neurodegenerative diseases.
http://www.ncbi.nlm.nih.gov/pubmed/24047617

Prevention of juvenile hydrocephalus by decorin treatment
Scarring in the subarachnoid space, as occurs following intraventricular hemorrhage in premature infants, plays a key role in the development of hydrocephalus. Permanent shunting is typically needed to protect the developing brain from further damage, but the frequency of shunt obstruction and infection present an opportunity for improved therapy. TGF-β has been implicated in various models of inflammatory fibrosis, leading Botfield et al. to hypothesize that decorin, a TGF-β inhibitor, might prevent the development of hydrocephalus. Hydrocephalus was induced in a juvenile rat model via kaolin injection. Then, an ALZET pump (Model 2002) was implanted subcutaneously and connected to an MRI-compatible intraventricular cannula for chronic infusion of decorin or vehicle (3 or 14 days). According to Botfield, “the wide distribution of decorin throughout the subarachnoid space confirmed successful delivery.” Further tissue analysis showed that decorin reduced TGF-β and other markers of fibrosis. MRI after 14 days demonstrated that decorin preserved ventricular volumes following kaolin injection, proof that it prevented the development of communicating hydrocephalus in this model.
Brain 2013;136:2842-2858

Intrathecal baclofen therapy for traumatic brain injury
Spasticity following traumatic brain injury (TBI) is a significant problem, yet current guidelines preclude the use of intrathecal baclofen (ITB), an antispastic, during the first year following injury. Bose et al. used ALZET pumps to evaluate the effectiveness of acute ITB on spasticity in a rat model of TBI. Starting one week after injury, each animal was treated for 4 weeks with either ITB (0.8 µg/hr) or saline using a subcutaneously implanted ALZET pump (Model 2004) connected to an intrathecal catheter inserted at L2. Early treatment with ITB prevented early onset spasticity and reduced late onset spasticity (as measured by lower limb joint torques) without adversely affecting cognition and balance.
Journal of Neurotrauma 2013;30:1177-1191

Calcium reduction improves nerve recovery
Nerve trauma induces excessive accumulation of Ca2+, exacerbating the injury and preventing nerve regeneration. Yan et al. evaluated the effect of continuous treatment with calcium modulating agents on peripheral nerve recovery. Sprague-Dawley rats were subjected to sciatic nerve crush injury; then treated with nifedipine, calcitonin, or saline using ALZET pumps (Model 2006). Solutions were delivered directly to the nerve injury site over 4 weeks via a fenestrated-tip catheter connected to the pump. Nifedipine and calcitonin treatment significantly improved functional nerve recovery rates compared to controls. Calcium intensity at the injury site was indicative of the degree of nerve injury, and calcium absorption rate strongly correlates with nerve recovery rate. The study shows that reduction of calcium influx and accumulation protects nerves from further degeneration and speeds regeneration. ALZET pumps provided an effective means for delivering calcium absorption medications, ensuring constant therapeutic levels at the nerve injury site, and avoiding adverse effects seen with systemic treatment. Yan et al. suggest that treatment should be given early and consistently until complete nerve regeneration is achieved.
Journal of Neuroscience Methods 2013;217:54-62

Protective effect of deferoxamine infusion
Iron is known to accumulate in the brains of Huntington’s disease (HD) patients and mouse disease models. Chen et al. designed studies to investigate the location of iron accumulation, and its significance on pathogenesis in mouse models of HD. Brain imaging studies showed accumulation of redox-active iron in the endolysosomal compartment of HD neurons, which had increased susceptibility to iron-associated oxidative stress. R6/2 HD mice were then implanted with ALZET pumps (Model 1002) and brain cannulae to enable direct ICV administration of deferoxamine, an iron chelator which completely silences iron redox activity. An improvement of the motor phenotype was evident after a 2-week dosing period with deferoxamine, validating the protective effect of iron chelation in R6/2 HD mice.
PLoS One 2013;8(10):e77023

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What researchers are saying...

“Considering the secretion rate of CSF in rats (120 to 320 ul/h), this low rate of infusion – 0.5µl/h – was not likely to affect CSF pressure.” Wang et al., Hypertension 2002;40:96-100.