Antonio Noronha

Alcohol‐Induced Neurodegeneration: When, Where and Why?

This manuscript reviews the proceedings of a symposium organized by Drs. Antonio Noronha and Fulton Crews presented at the 2003 Research Society on Alcoholism meeting. The purpose of the symposium was to examine recent findings on when alcohol induced brain damage occurs, e.g., during intoxication and/or during alcohol withdrawal. Further studies investigate specific brain regions (where) and the mechanisms (why) of alcoholic neurodegeneration. The presentations were (1) Characterization of Synaptic Loss in Cerebella of Mature and Senescent Rats after Lengthy Chronic Ethanol Consumption, (2) Ethanol Withdrawal Both Causes Neurotoxicity and Inhibits Neuronal Recovery Processes in Rat Organotypic Hippocampal Cultures, (3) Binge Drinking-Induced Brain Damage: Genetic and Age Related Effects, (4) Binge Ethanol-Induced Brain Damage: Involvement of Edema, Arachidonic Acid and Tissue Necrosis Factor alpha (TNFalpha), and (5) Cyclic AMP Cascade, Stem Cells and Ethanol. Taken together these studies suggest that alcoholic neurodegeneration occurs through multiple mechanisms and in multiple brain regions both during intoxication and withdrawal.

Medications development to treat alcohol dependence: a vision for the next decade

More than 76 million people world‐wide are estimated to have diagnosable alcohol use disorders (AUDs) (alcohol abuse or dependence), making these disorders a major global health problem. Pharmacotherapy offers promising means for treating AUDs, and significant progress has been made in the past 20 years. The US Food and Drug Administration approved three of the four medications for alcoholism in the last two decades. Unfortunately, these medications do not work for everyone, prompting the need for a personalized approach to optimize clinical benefit or more efficacious medications that can treat a wider range of patients, or both. To promote global health, the potential reorganization of the National Institutes of Health (NIH) must continue to support the National Institute on Alcohol Abuse and Alcoholisms (NIAAAs) vision of ensuring the development and delivery of new and more efficacious medications to treat AUDs in the coming decade. To achieve this objective, the NIAAA Medications Development Team has identified three fundamental long‐range goals: (1) to make the drug development process more efficient; (2) to identify more efficacious medications, personalize treatment approaches, or both; and (3) to facilitate the implementation and adaptation of medications in real‐world treatment settings. These goals will be carried out through seven key objectives. This paper describes those objectives in terms of rationale and strategy. Successful implementation of these objectives will result in the development of more efficacious and safe medications, provide a greater selection of therapy options and ultimately lessen the impact of this devastating disorder.

Molecular specificity of L2 monoclonal antibodies that bind to carbohydrate determinants of neural cell adhesion molecules and their resemblance to other monoclonal antibodies recognizing the myelin-associated glycoprotein.

L2 monoclonal antibodies and HNK-1 have been shown to bind to related carbohydrate determinants in the myelin-associated glycoprotein (MAG) and several adhesion molecules of the nervous system including neural cell adhesion molecule (N-CAM), L1 and J1. It is shown here that MAG is the principal component in human white matter binding the L2 antibodies, but the most prominent antigens with the L2 epitopes in human gray matter are of higher Mr. It is also shown that the L2 antibodies resemble HNK-1 in binding to some 19-28 kDa glycoproteins and some sulfated, glucuronic acid-containing sphingoglycolipids of the peripheral nervous system (PNS). In addition, monoclonal and polyclonal antibodies raised to human MAG are shown to cross react with bovine N-CAM due to the presence of common carbohydrate constituents. The results further emphasize the shared antigenicity between MAG, N-CAM and other adhesion molecules. In addition, they demonstrate that the L2 antibodies belong to a family of monoclonal antibodies (including HNK-1, human IgM paraproteins associated with neuropathy, and others) that are characterized by reactivity against carbohydrate determinants shared by human MAG, the 19-28 kDa glycoproteins of the PNS and the sulfated, glucuronic acid-containing sphingoglycolipids of the PNS.

Generation and characterization of mouse monoclonal antibodies to the myelin-associated glycoprotein (MAG)

A panel of mouse monoclonal antibodies to rat and human myelin-associated glycoprotein (MAG) was developed. Normal mice were unresponsive to rat MAG, and successful immunization with rat MAG was only achieved in autoimmune NZB mice. By contrast, all strains of mice were responsive to human MAG. The monoclonal antibodies developed differ with respect to immunoglobulin type, their specificity for human and/or rat MAG, and their recognition of protein or carbohydrate epitopes in MAG. In general, the antibodies that react with the protein backbone recognize both rat and human MAG, whereas a large number of the monoclonal antibodies recognize a carbohydrate determinant in human MAG that is not in rat MAG. Immunocytochemical staining of adult human spinal cord with the monoclonal antibodies resulted in periaxonal staining of myelin sheaths, similar to that produced by well-defined, rabbit, polyclonal anti-MAG serum. In addition, the antibodies recognizing, carbohydrate determinants in human MAG strongly stained oligodendrocyte cytoplasm. These monoclonal antibodies will be of value for the further chemical and biological characterization of MAG.

A human lymphocyte antigen is shared with a group of glycoproteins in peripheral nerve

The monoclonal antibody HNK-1 binds to a carbohydrate determinant in the myelin-associated glycoprotein (MAG) and other glycoproteins of human peripheral nerve. Some glycoproteins of lower Mr than the major P0 glycoprotein of myelin appear to bind more antibody than MAG. These glycoproteins electrophorese in the Mr range of 20,000 to 26,000 and are present in the purified myelin fraction. The results indicate that an antigen on the surface of a subset of lymphocytes is shared with a group of glycoproteins in human peripheral nerve. The antigen appears to be similar to that recognized by IgM paraproteins associated with a type of neuropathy.

New insights on neurobiological mechanisms underlying alcohol addiction

Alcohol dependence/addiction is mediated by complex neural mechanisms that involve multiple brain circuits and neuroadaptive changes in a variety of neurotransmitter and neuropeptide systems. Although recent studies have provided substantial information on the neurobiological mechanisms that drive alcohol drinking behavior, significant challenges remain in understanding how alcohol-induced neuroadaptations occur and how different neurocircuits and pathways cross-talk. This review article highlights recent progress in understanding neural mechanisms of alcohol addiction from the perspectives of the development and maintenance of alcohol dependence. It provides insights on cross talks of different mechanisms and reviews the latest studies on metaplasticity, structural plasticity, interface of reward and stress pathways, and cross-talk of different neural signaling systems involved in binge-like drinking and alcohol dependence.

Myelin-Associated Glycoprotein Shares an Antigenic Determinant with a Glycoprotein of Human Melanoma Cells

Abstract A sulfated 100K‐dalton glycoprotein has been shown to be released into the culture medium of melanoma cells. Monoclonal antibodies 10C5 and 11B5, which were raised to human melanoma cells, as well as HNK‐1 bind to this glycoprotein. It is shown here that mouse anti‐myelin‐associated glycoprotein (MAG) carbohydrate antibodies raised to human MAG and a human IgM paraprotein associated with neuropathy also bind to the same 100K molecule. However, anti‐MAG antibodies recognizing peptide epitopes do not appear to react with this glycoprotein of melanoma cells, a result suggesting that its similarity to MAG is restricted to shared carbohydrate moieties. The anti‐melanoma antibodies (10C5 and 11B5) resemble HNK‐1 in binding to MAG and to some 19–28K‐dalton glycoproteins and sulfated, glucuronic acid‐containing sphingoglycolipids of the peripheral nervous system (PNS). In addition, the anti‐melanoma antibodies cross‐react with neural cell adhesion molecule (N‐CAM), an observation emphasizing the shared antigenicity between MAG and other adhesion molecules. The results demonstrate that the anti‐melanoma antibodies fall into a class of monoclonal antibodies (including HNK‐1, human IgM paraproteins associated with neuropathy, anti‐human MAG antibodies, and L2 antibodies) that are characterized by reactivity against related carbohydrate determinants shared by human MAG, N‐CAM, and several protein and lipid glyco‐conjugates of the PNS.

Neurobiology of Alcohol Dependence

In recent years, alcoholism has emerged as one of the major addiction disorders worldwide. Alterations in gene expression together with environmental factors have been shown to play a crucial role in the development of alcoholism. A common thread that links these different phenomena is epigenetics, which may be defined as genetic modifications that occur in the absence of DNA sequence changes. Recent in vitro and in vivo data have shown that different epigenetic modifications can occur in response to both acute and chronic alcohol exposure. These changes can affect gene expression and ultimately brain circuitry that control alcohol tolerance, withdrawal, and dependence. Epigenetic modifications such as DNA methylation, histone acetylation and methylation, and microRNA (miRNA) regulation play a role in alcoholism via mediating effects of alcohol in different tissues or altering alcohol intake. This review focuses on the most current brain research in the rapidly growing field of epigenetics and alcoholism.In recent years, alcoholism has emerged as one of the major addiction disorders worldwide. Alterations in gene expression together with environmental factors have been shown to play a crucial role in the development of alcoholism. A common thread that links these different phenomena is epigenetics, which may be defined as genetic modifications that occur in the absence of DNA sequence changes. Recent in vitro and in vivo data have shown that different epigenetic modifications can occur in response to both acute and chronic alcohol exposure. These changes can affect gene expression and ultimately brain circuitry that control alcohol tolerance, withdrawal, and dependence. Epigenetic modifications such as DNA methylation, histone acetylation and methylation, and microRNA (miRNA) regulation play a role in alcoholism via mediating effects of alcohol in different tissues or altering alcohol intake. This review focuses on the most current brain research in the rapidly growing field of epigenetics and alcoholism.

The myelin-associated glycoprotein is phosphorylated in the peripheral nervous system.

Phosphorylation of the myelin-associated glycoprotein (MAG) in the peripheral nervous system is demonstrated by immunoprecipitation from myelin proteins radiolabeled in vivo, in nerve slices and in a cell-free system. Phosphoamino acid analysis of immunoprecipitated MAG revealed the presence of radioactivity in phosphoserine, but not in phosphothreonine or phosphotyrosine. Only the shorter isoform of MAG (S-MAG) was detected by immunostaining of nitrocellulose sheets with anti-MAG anti-serum after enzymatic deglycosylation of immunoprecipitated MAG labeled in nerve slices. Autoradiography of the same Western blots revealed that most of the radioactive phosphate was in S-MAG, demonstrating that the polypeptide backbone of S-MAG is phosphorylated in the PNS.

The conception of the ABCD study: From substance use to a broad NIH collaboration

Adolescence is a time of dramatic changes in brain structure and function, and the adolescent brain is highly susceptible to being altered by experiences like substance use. However, there is much we have yet to learn about how these experiences influence brain development, how they promote or interfere with later health outcomes, or even what healthy brain development looks like. A large longitudinal study beginning in early adolescence could help us understand the normal variability in adolescent brain and cognitive development and tease apart the many factors that influence it. Recent advances in neuroimaging, informatics, and genetics technologies have made it feasible to conduct a study of sufficient size and scope to answer many outstanding questions. At the same time, several Institutes across the NIH recognized the value of collaborating in such a project because of its ability to address the role of biological, environmental, and behavioral factors like gender, pubertal hormones, sports participation, and social/economic disparities on brain development as well as their association with the emergence and progression of substance use and mental illness including suicide risk. Thus, the Adolescent Brain Cognitive Development study was created to answer the most pressing public health questions of our day.