Medical Neurobiology Commons^™

Nasal Accumulation And Metabolism Of Δ9-Tetrahydrocannabinol Following Aerosol (‘Vaping’) Administration In An Adolescent Rat Model, Alexa Torrens, Christina M Ruiz, Maricela X Martinez, Alex Mabou Tagne, Pritam Roy, Dakota Grimes, Faizy Ahmed, Valeria Lallai, Victoria Inshishian, Malia Bautista, Yen-Chu Chen, Marilyn A. Huestis, Aditi Das, Christie D Fowler, Stephen V Mahler, Daniele Piomelli

Institute of Emerging Health Professions Faculty Papers

Passive aerosol exposure to Δ9-tetrahydrocannabinol (THC) in laboratory animals results in faster onset of action and less extensive liver metabolism compared to most other administration routes and might thus provide an ecologically relevant model of human cannabis inhalation. Previous studies have, however, overlooked the possibility that rodents, as obligate nose breathers, may accumulate aerosolized THC in the nasal cavity, from where the drug might directly diffuse to the brain. To test this, we administered THC (ten 5-s puffs of 100 mg/mL of THC) to adolescent (31-day-old) Sprague-Dawley rats of both sexes. We used liquid chromatography/tandem mass spectrometry to quantify the …

Hyccin, The Molecule Mutated In The Leukodystrophy Hypomyelination And Congenital Cataract (Hcc), Is A Neuronal Protein., Elisabetta Gazzerro, Simona Baldassari, Caterina Giacomini, Veronica Musante, Floriana Fruscione, Veronica La Padula, Roberta Biancheri, Sonia Scarfì, Valeria Prada, Federica Sotgia, Ian D Duncan, Federico Zara, Hauke B Werner, Michael P Lisanti, Lucilla Nobbio, Anna Corradi, Carlo Minetti

Kimmel Cancer Center Faculty Papers

"Hypomyelination and Congenital Cataract", HCC (MIM #610532), is an autosomal recessive disorder characterized by congenital cataract and diffuse cerebral and peripheral hypomyelination. HCC is caused by deficiency of Hyccin, a protein whose biological role has not been clarified yet. Since the identification of the cell types expressing a protein of unknown function can contribute to define the physiological context in which the molecule is explicating its function, we analyzed the pattern of Hyccin expression in the central and peripheral nervous system (CNS and PNS). Using heterozygous mice expressing the b-galactosidase (LacZ) gene under control of the Hyccin gene regulatory elements, …

Early Versus Delayed Decompression For Traumatic Cervical Spinal Cord Injury: Results Of The Surgical Timing In Acute Spinal Cord Injury Study (Stascis), Michael G. Fehlings, Alexander Vaccaro, Jefferson R. Wilson, Anoushka Singh, David W. Cadotte, James S. Harrop, Bizhan Aarabi, Christopher Shaffrey, Marcel Dvorak, Charles Fisher, Paul Arnold, Eric M. Massicotte, Stephen Lewis, Raja Rampersaud

Department of Neurosurgery Faculty Papers

Background: There is convincing preclinical evidence that early decompression in the setting of spinal cord injury (SCI) improves neurologic outcomes. However, the effect of early surgical decompression in patients with acute SCI remains uncertain. Our objective was to evaluate the relative effectiveness of early (,24 hours after injury) versus late ($24 hours after injury) decompressive surgery after traumatic cervical SCI.

Methods: We performed a multicenter, international, prospective cohort study (Surgical Timing in Acute Spinal Cord Injury Study: STASCIS) in adults aged 16–80 with cervical SCI. Enrolment occurred between 2002 and 2009 at 6 North American centers. The primary outcome was …

Functional Recovery Of Untreated Human Immunodeficiency Virus-Associated Guillain-Barré Syndrome: A Case Report, Adam L. Schreiber, John W. Norbury Iii, Eduardo A. De Sousa

Department of Rehabilitation Medicine Faculty Papers

HIV-associated Guillain-Barré Syndrome is a well-documented phenomenon, typically occurring at seroconversion. GBS may result in functional impairment treated with a combination of medications, plasmapheresis, and rehabilitation. The quantified functional recovery of HIV-associated GBS with or without HIV treatment is not well-described. Utilizing serial FIM scoring, we describe a patient’s recovery from HIV-associated GBS after treatment with IVIg and acute inpatient rehabilitation without HIV treatment.

Acute Effects Of A Selective Cannabinoid-2 Receptor Agonist On Neuroinflammation In A Model Of Traumatic Brain Injury., Melanie B Elliott, Ronald F Tuma, Peter S Amenta, Mary F Barbe, Jack I Jallo

Department of Neurosurgery Faculty Papers

Proposed therapeutic strategies for attenuating secondary traumatic brain injury (TBI) include modulation of acute neuroimmune responses. The goal of this study was to examine the acute effects of cannabinoid-2 receptor (CB(2)R) modulation on behavioral deficits, cerebral edema, perivascular substance P, and macrophage/microglial activation in a murine model of TBI. Thirty male C57BL/6 mice underwent sham surgery, or cortical contusion impact injury (CCI). CCI mice received vehicle or the CB(2)R agonist 0-1966 at 1 and 24 h after injury. Performance on the rotarod, forelimb cylinder, and open-field tests were evaluated before and at 48 h after sham or CCI surgery. Cerebral …

A Phase I/Iia Clinical Trial Of A Recombinant Rho Protein Antagonist In Acute Spinal Cord Injury., Michael G Fehlings, Nicholas Theodore, James Harrop, Gilles Maurais, Charles Kuntz, Chris I Shaffrey, Brian K Kwon, Jens Chapman, Albert Yee, Allyson Tighe, Lisa Mckerracher

Department of Neurosurgery Faculty Papers

Multiple lines of evidence have validated the Rho pathway as important in controlling the neuronal response to growth inhibitory proteins after central nervous system (CNS) injury. A drug called BA-210 (trademarked as Cethrin(®)) blocks activation of Rho and has shown promise in pre-clinical animal studies in being used to treat spinal cord injury (SCI). This is a report of a Phase I/IIa clinical study designed to test the safety and tolerability of the drug, and the neurological status of patients following the administration of a single dose of BA-210 applied during surgery following acute SCI. Patients with thoracic (T2-T12) or …

Fus Transgenic Rats Develop The Phenotypes Of Amyotrophic Lateral Sclerosis And Frontotemporal Lobar Degeneration., Cao Huang, Hongxia Zhou, Jianbin Tong, Han Chen, Yong-Jian Liu, Dian Wang, Xiaotao Wei, Xu-Gang Xia

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Fused in Sarcoma (FUS) proteinopathy is a feature of frontotemporal lobar dementia (FTLD), and mutation of the fus gene segregates with FTLD and amyotrophic lateral sclerosis (ALS). To study the consequences of mutation in the fus gene, we created transgenic rats expressing the human fus gene with or without mutation. Overexpression of a mutant (R521C substitution), but not normal, human FUS induced progressive paralysis resembling ALS. Mutant FUS transgenic rats developed progressive paralysis secondary to degeneration of motor axons and displayed a substantial loss of neurons in the cortex and hippocampus. This neuronal loss was accompanied by ubiquitin aggregation and …

Ms4a4b, A Cd20 Homologue In T Cells, Inhibits T Cell Propagation By Modulation Of Cell Cycle., Hui Xu, Yaping Yan, Mark S Williams, Gregory B Carey, Jingxian Yang, Hongmei Li, Guang-Xian Zhang, Abdolmohamad Rostami

Department of Neurology Faculty Papers

MS4a4B, a CD20 homologue in T cells, is a novel member of the MS4A gene family in mice. The MS4A family includes CD20, FcεRIβ, HTm4 and at least 26 novel members that are characterized by their structural features: with four membrane-spanning domains, two extracellular domains and two cytoplasmic regions. CD20, FcεRIβ and HTm4 have been found to function in B cells, mast cells and hematopoietic cells respectively. However, little is known about the function of MS4a4B in T cell regulation. We demonstrate here that MS4a4B negatively regulates mouse T cell proliferation. MS4a4B is highly expressed in primary T cells, natural …

Dopaminergic Neurons Derived From Human Induced Pluripotent Stem Cells Survive And Integrate Into 6-Ohda-Lesioned Rats., Jingli Cai, Ming Yang, Elizabeth Poremsky, Sarah Kidd, Jay S Schneider, Lorraine Iacovitti

Farber Institute for Neuroscience Faculty Papers

Cell replacement therapy could be an important treatment strategy for Parkinson's disease (PD), which is caused by the degeneration of dopamine neurons in the midbrain (mDA). The success of this approach greatly relies on the discovery of an abundant source of cells capable of mDAergic function in the brain. With the paucity of available human fetal tissue, efforts have increasingly focused on renewable stem cells. Human induced pluripotent stem (hiPS) cells offer great promise in this regard. If hiPS cells can be differentiated into authentic mDA neuron, hiPS could provide a potential autologous source of transplant tissue when generated from …

Multiport Minimally Invasive Skull Base Surgery: How Many Ports Are Too Many?, Yaron A. Moshel, Theodore H. Schwartz

Department of Neurosurgery Faculty Papers

Surgical access to the ventral skull base has evolved considerably over the past several years with the introduction of minimally invasive endoscopic and endoscope-assisted approaches. The accompanying manuscript by Ciporen et al. demonstrates an addition to this growing body of literature in their description of the feasibility of multiportal endoscopic approaches to the skull base, particularly the precaruncular transorbital approach, in a series of cadaver dissections. Similar to laparoscopic abdominal surgery, which utilizes multiple small ports to improve visualization and manipulation, they envision a modular combination of approaches that allows an endoscope to be placed in one port and surgery …

Interaction Of The Mu-Opioid Receptor With Gpr177 (Wntless) Inhibits Wnt Secretion: Potential Implications For Opioid Dependence., Jay Jin, Saranya Kittanakom, Victoria Wong, Beverly A S Reyes, Elisabeth J Van Bockstaele, Igor Stagljar, Wade Berrettini, Robert Levenson

Department of Neurosurgery Faculty Papers

BACKGROUND: Opioid agonist drugs produce analgesia. However, long-term exposure to opioid agonists may lead to opioid dependence. The analgesic and addictive properties of opioid agonist drugs are mediated primarily via the mu-opioid receptor (MOR). Opioid agonists appear to alter neuronal morphology in key brain regions implicated in the development of opioid dependence. However, the precise role of the MOR in the development of these neuronal alterations remains elusive. We hypothesize that identifying and characterizing novel MOR interacting proteins (MORIPs) may help to elucidate the underlying mechanisms involved in the development of opioid dependence. RESULTS: GPR177, the mammalian ortholog of Drosophila …

Mitochondrial Mislocalization Underlies Abeta42-Induced Neuronal Dysfunction In A Drosophila Model Of Alzheimer's Disease., Kanae Iijima-Ando, Stephen A Hearn, Christopher Shenton, Anthony Gatt, Lijuan Zhao, Koichi Iijima

Department of Biochemistry and Molecular Biology Faculty Papers

The amyloid-beta 42 (Abeta42) is thought to play a central role in the pathogenesis of Alzheimer's disease (AD). However, the molecular mechanisms by which Abeta42 induces neuronal dysfunction and degeneration remain elusive. Mitochondrial dysfunctions are implicated in AD brains. Whether mitochondrial dysfunctions are merely a consequence of AD pathology, or are early seminal events in AD pathogenesis remains to be determined. Here, we show that Abeta42 induces mitochondrial mislocalization, which contributes to Abeta42-induced neuronal dysfunction in a transgenic Drosophila model. In the Abeta42 fly brain, mitochondria were reduced in axons and dendrites, and accumulated in the somata without severe mitochondrial …

Development Of A Mouse Monoclonal Antibody Cocktail For Post-Exposure Rabies Prophylaxis In Humans., Thomas Müller, Bernhard Dietzschold, Hildegund Ertl, Anthony R Fooks, Conrad Freuling, Christine Fehlner-Gardiner, Jeannette Kliemt, Francois X Meslin, Charles E Rupprecht, Noël Tordo, Alexander I Wanderler, Marie Paule Kieny

Department of Microbiology and Immunology Faculty Papers

As the demand for rabies post-exposure prophylaxis (PEP) treatments has increased exponentially in recent years, the limited supply of human and equine rabies immunoglobulin (HRIG and ERIG) has failed to provide the required passive immune component in PEP in countries where canine rabies is endemic. Replacement of HRIG and ERIG with a potentially cheaper and efficacious alternative biological for treatment of rabies in humans, therefore, remains a high priority. In this study, we set out to assess a mouse monoclonal antibody (MoMAb) cocktail with the ultimate goal to develop a product at the lowest possible cost that can be used …

The Efficacy Of Surgical Decompression Before 24 Hours Versus 24 To 72 Hours In Patients With Spinal Cord Injury From T1 To L1--With Specific Consideration On Ethics: A Randomized Controlled Trial., Vafa Rahimi-Movaghar, Soheil Saadat, Alexander R Vaccaro, Seyed Mohammad Ghodsi, Mohammad Samadian, Arya Sheykhmozaffari, Seyed Mohammad Safdari, Bahram Keshmirian

Department of Neurosurgery Faculty Papers

BACKGROUND: There is no clear evidence that early decompression following spinal cord injury (SCI) improves neurologic outcome. Such information must be obtained from randomized controlled trials (RCTs). To date no large scale RCT has been performed evaluating the timing of surgical decompression in the setting of thoracolumbar spinal cord injury. A concern for many is the ethical dilemma that a delay in surgery may adversely effect neurologic recovery although this has never been conclusively proven. The purpose of this study is to compare the efficacy of early (before 24 hours) verse late (24-72 hours) surgical decompression in terms of neurological …

Abeta42 Mutants With Different Aggregation Profiles Induce Distinct Pathologies In Drosophila., Koichi Iijima, Hsueh-Cheng Chiang, Stephen A Hearn, Inessa Hakker, Anthony Gatt, Christopher Shenton, Linda Granger, Amy Leung, Kanae Iijima-Ando, Yi Zhong

Department of Biochemistry and Molecular Biology Faculty Papers

Aggregation of the amyloid-beta-42 (Abeta42) peptide in the brain parenchyma is a pathological hallmark of Alzheimer's disease (AD), and the prevention of Abeta aggregation has been proposed as a therapeutic intervention in AD. However, recent reports indicate that Abeta can form several different prefibrillar and fibrillar aggregates and that each aggregate may confer different pathogenic effects, suggesting that manipulation of Abeta42 aggregation may not only quantitatively but also qualitatively modify brain pathology. Here, we compare the pathogenicity of human Abeta42 mutants with differing tendencies to aggregate. We examined the aggregation-prone, EOFAD-related Arctic mutation (Abeta42Arc) and an artificial mutation (Abeta42art) that …

Spinal Cord Stimulation: An Update., Steven Falowski, Amanda Celii, Ashwini Sharan

Department of Neurosurgery Faculty Papers

Spinal cord stimulation has been used in the treatment of many chronic pain disorders since 1967. In this update, the indications for spinal cord stimulation are reviewed with attention to recent publications. A focused review of the literature on abdominal and visceral pain syndromes is also provided. Furthermore, the technology has evolved from the use of monopolar electrodes to complex electrode arrays. Similarly, the power source has changed from a radio frequency-driven system to a rechargeable impulse generator. These topics are covered, along with a short discussion of implant technique. Finally, we include a review of complications of such therapy. …

Global Cns Gene Transfer For A Childhood Neurogenetic Enzyme Deficiency: Canavan Disease., Paola Leone, Christopher G Janson, Scott J Mcphee, Matthew J During

Department of Neurosurgery Faculty Papers

The neurogenetic prototypic disease on which we chose to test our gene therapy strategy is Canavan disease (CD). CD is an autosomal recessive leukodystrophy associated with spongiform degeneration of the brain. At present the disease is uniformly fatal in affected probands. CD is characterized by mutations in the aspartoacylase (ASPA) gene, resulting in loss of enzyme activity. In this review, recent evidence is summarized on the etiology and possible treatments for CD. In particular, we discuss two gene delivery systems representing recent advances in both viral and liposome technology: a novel cationic liposome-polymer-DNA (LPD) complex, DCChol/DOPE-protamine, as well as recombinant …