Degeneration and regeneration of the nervous system

All cells in living organisms have a limited life span, and when the time set by their biological clocks has run out, they will die , their highly orga­ nized macromolec ular structure will disintegrate, and the low-molec ul ar degrad ation products be­ come part of the disorder of the surroundings . In thermodynamic terms, this series of events consti­ tutes what has been c alled the entropic doom. We know little about those molec ul ar mechanisms that limit the life span of cells in the absence of dise ase. For the clinician, therefore, the important task is to prevent or tre at dise ases that jeopardize the proper functioning and viability of cells whose biologic al clocks have not yet run out . Measures instituted to prevent brain cell death have a special importance . This i s partly due t o the fact that w e equate human life with the functioning of the brain. However, this importance also resides in the v ulnerability of brain cells to conditions that allow cells of most other tissue to survive , and to continue or res ume their activitie s . The clinically most important conditions leading to brain cell death are those associated with cere­ brovascul ar dise ase, particularly stroke, and with head trauma. We will begin, though, by rec alling the traditional view of the occ urrence and loc alization of neuronal damage in four conditions that lead to more disseminated alterations, e specially since they have been considered to c ause nerve cell injury of a

https://journals.sagepub.com/doi/pdf/10.1038/jcbfm.1981.18

Cell Damage in the Brain: A Speculative Synthesis

Mammalian multidrug resistance gene: Complete cDNA sequence indicates strong homology to bacterial transport proteins

The plasma membranes of hamster, mouse, and human tumor cell lines that display multiple resistance to drugs were examined by gel electrophoresis and immunoblotting. In every case, increased expression of a 170,000-dalton surface antigen was found to be correlated with multidrug resistance. This membrane component is of identical molecular size and shares some immunogenic homology with the previously characterized P-glycoprotein of colchicine-resistant Chinese hamster ovary cells. This finding may have application to cancer therapy.

https://science.sciencemag.org/content/sci/221/4617/1285.full.pdf

Cell surface P-glycoprotein associated with multidrug resistance in mammalian cell lines.

An Endocrine Society Clinical Practice Guideline Endocrine and Nutritional Management of the Post-Bariatric Surgery Patient:

Vasoactive intestinal polypeptide immunoreactivity is present in high concentrations in clonal lines of neuronal and glial origin. The central nervous system and sympathetic ganglia are also rich in the peptide. The findings suggest that this peptide, hitherto thought limited to the gastrointestinal tract, is widely distributed in neural tissue and may have broad physiological significance.

https://science.sciencemag.org/content/sci/192/4242/907.full.pdf

Vasoactive intestinal polypeptide: abundant immunoreactivity in neural cell lines and normal nervous tissue.

The specific activity of mouse neuroblastoma acetylcholinesterase (EC 3.1.1.7) increased 25-fold when the rate of cell division was restricted. The results show that acetylcholinesterase activity is regulated in neuroblastoma cells and that the regulatory mechanism is inversely related to the rate of cell division. Under the same conditions the specific activity of catechol-O-methyl transferase (EC 2.1.1.6) did not change significantly.

https://www.pnas.org/content/pnas/67/2/786.full.pdf

Regulation of Acetylcholinesterase in Neuroblastoma Cells

An autosomal dominant striatonigral degeneration is present in a family of Portuguese ancestry numbering in excess of 329 persons in eight generations. The illness begins in the second, third, or fourth decade, and progresses for about 15 years with parkinsonian rigidity, spasticity, spastic dysarthria, and abnormalities of eye movement. Neuropathologic findings are severe neuronal loss and astrocytic gliosis in the corpus striatum and substantia nigra, with a moderate neuronal loss in the dentate nucleus of the cerebellum and nucleus ruber of the midbrain. This is a new genetic entity, distinct from other autosomal dominant neurologic disorders such as nigrospinodentatal degeneration, olivopontocerebellar degeneration, dystonia musculorum deformans, Machado's disease, and Huntington's disease.

Autosomal dominant striatonigral degeneration: A clinical, pathologic, and biochemical study of a new genetic disorder

A series of increasingly drug-resistant cell populations were selected and cloned from C-46 murine neuroblastoma with the chemotherapeutic drugs maytansine, vincristine, adriamycin, or Baker's antifol. All clones demonstrated reciprocal cross-resistance to these structurally and functionally diverse drugs and failed to accumulate radiolabeled vincristine, colchicine, or Baker's antifol despite normal drug binding to cell homogenates. Initial isolates of drug-resistant populations were genetically unstable, rapidly reverting to a drug-sensitive phenotype when grown without drug, at 0.05 reversion per cell division. After prolonged growth in drug, this drug-resistant genotype stabilized. Mean chromosome number increased 300% in an initially isolated 20-fold maytansine-resistant clone, which also displayed numerous double-minute chromosomes. Descendants 240-fold more resistant than the parent, also unstable, possessed the wild-type complement of 80 chromosomes, but 45% of these cells possessed 24 double-minute chromosomes per cell; such chromosomes were absent from the drug-sensitive parental clone. Only 1.0 and 1.2 double-minute chromosomes per cell were seen in a 7-fold stably resistant revertant or 1200-fold stably resistant descendants, respectively. Double-minute chromosomes containing amplified genes for the drug target dihydrofolate reductase (tetrahydrofolate dehydrogenase; 5,6,7,8-tetrahydrofolate:NADP+ oxidoreductase, EC 1.5.1.3) have been reported in an unstable methotrexate-resistant R1-A sarcoma. These extrachromosomal gene copies were absent in stably resistant progeny. The presence of similar particles in unstably drug-resistant uptake mutants of neuroblastoma and their diminution in stably resistant descendants supports and extends their possible role in the rapid onset and instability of epigenetic drug resistance in cancer chemotherapy.

https://www.pnas.org/content/pnas/78/6/3654.full.pdf

Correlation of double-minute chromosomes with unstable multidrug cross-resistance in uptake mutants of neuroblastoma cells

Three months after gastric partitioning for morbid obesity, two patients developed an unusual and severe form of polyneuropathy that affected their sense of position maximally. This disord...

Roger N. Rosenberg

Papers

Vasoactive intestinal polypeptide: abundant immunoreactivity in neural cell lines and normal nervous tissue.

Regulation of Acetylcholinesterase in Neuroblastoma Cells

Autosomal dominant striatonigral degeneration: A clinical, pathologic, and biochemical study of a new genetic disorder

Correlation of double-minute chromosomes with unstable multidrug cross-resistance in uptake mutants of neuroblastoma cells

Peripheral Neuropathy and Starvation After Gastric Partitioning for Morbid Obesity