Hamdan Medical Journal (previously the Journal of Medical Sciences)

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Protecting the Brain from Aging and Insult

James W Simpkins
Published in : Journal of Medical Sciences ; Vol 1, No 1 (2008)
DOI : 10.2174/1996327000801010029


Age-related decline in noradrenergic neuronal activity in a rat model and the characterization of its role in reproductive senescence were first described in 1977.1,2 These studies documented the detrimental effects of aging on both noradrenergic and dopaminergic systems and demonstrated the importance of preservation of brain function during the aging process on reproductive function.

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Simpkins JW, Mueller GP, Huang HH, Meites J. Evidence for depressed catecholamine and enhanced serotonin metabolism in aging male rats: possible relation to gonadotropin secretion. Endocrinology, 1977; 100:1672-1678.

Simpkins JW, Huang HH, Advis JP, Meites J. Evaluation of changes in NE and DA turnover during progesterone induced LH and prolactin surges in ovariectomized, estrogen primed rats. Biology of Reproduction, 1979;20: 625-632.

Simpkins JW, Katovich MJ, Song I-C. Similarities between morphine withdrawal in the rat and the menopausal hot flush. Life Science, 1983; 32: 1957-1966.

Bodor N, Simpkins JW. Brain-specific, sustained release of dopamine with a redox delivery system. Science, 1983; 221: 65-67.

Bodor N, Prokai L, Wu W-M, Farag H, Jonalagadds S, Kawamura M, et al. A strategy for delivering peptides into the central nervous system by sequential metabolism.

Science, 1992; 257: 1698-1700.

Simpkins JW, McCornack J, Estes KS, Brewster ME, Shek E, Bodor N. Sustained brain-specific delivery of estradiol causes long-term suppression of luteinizing hormone

secretion. J Med Chem, 1986; 29: 1809-1812.

Rahimy MH, Bodor N, Simpkins JW. A rapid, sensitive method for the simultaneous quantitation of estradiol and estradiol conjugates in a variety of tissues: assay

development and evaluation of the distribution of a brain-enhanced estradiol-chemical delivery system. J Steroid Biochem, 1989; 33:179-187.

Anderson WR, Simpkins JW, Brewster ME, Bodor N. Evidence for prolonged suppression of stress-induced release of ACTH and corticosterone with a brainenhanced dexamethasone-redox delivery system. Neuroendocrinology, 1989; 50: 9-16.

Anderson WR, Rahimy MH, Brewster ME, Bodor N, Simpkins JW. The effects of a brain-enhanced estradiol delivery system on testosterone and androgen dependent tissue: II. The role of testosterone. Endocrinology, 1991;129: 726-733.

Rahimy MH, Anderson WR, Brewster ME, Bodor N, Simpkins JW. The effects of a brain-enhanced estradiol delivery system on testosterone and androgen dependent tissues: I. Dose-response and Time-course evaluation. Endocrinology, 1991; 129: 717-725.

Bishop J, Simpkins JW. Estradiol treatment increases viability of glioma and neuroblastoma cells in vitro. Molecular and Cellular Neuroscience, 1994; 5: 303-308.

Duff K, Petanceska S, Yu X, Wang R, Uljon S, Malester B, et al. Enhanced amyloidosis in response to ovariectomy in a transgenic model of Alzheimer’s disease. J

Neurochemistry, 2002; 80: 191-196.

Green PS, Gridley KE, Simpkins JW. Estradiol protects against amyloid-induced toxicity in SK-N-SH cells. Neuroscience Letters, 1996; 218: 165-168.

Green PS, Bishop J, Simpkins JW. 17 a-estradiol exerts neuroprotective effects on SK-N-SH cells. Journal Neuroscience, 1997a; 17: 511-515.

Green PS, Gordon K, Simpkins JW. Phenolic A ring requirement for the neuroprotective effects of steroids. J Steroid Biochemistry & Molecular Biology, 1997b; 63:


Perez EZ, Liu R, Yang SH, Cai ZY, Covey DF, Simpkins JW. Neuroprotective effects of an estratriene analog are estrogen receptor independent in vitro and in vivo. Brain Res, 2005; 1038(2):216-22.

Wang J, Green PS, Simpkins JW. Estradiol protects against ATP depletion, mitochondrial membrane potential decline and the generation of reactive oxygen species by

-nitropropionic acid in SK-N-SH human neuroblastoma cells. J Neurochemistry, 2001; 77: 804-811.

Wang X, Dykens JA, Perez E, Liu R, Yang S, Covey DF, et al. Neuroprotective effects of 17β-estradiol and nonfeminizing estrogens against H202 toxicity in human

neuroblastoma SK-N-SH cells. Mol Pharmacol, 2006; 70(1): 395-404.

Prokai L, Prokai-Tatrai K, Perjesi P, Zharikova A, Perez E, Liu R, et al. Quinol-based cyclic antioxidant mechanism in estrogen neuroprotection. Proc National Academy of Sciences USA, 2003; 100: 11741-11746.

Simpkins JW, Rajakumar G, Zhang YQ, Simpkins CE, Greenwald D, Yu CJ, et al. Estrogens reduce mortality and ischemic damage by middle cerebral artery occlusion in

the female rat. J Neurosurgery, 1997; 87: 724-730.

Simpkins JW, Yang SH, Liu R, Perez E, Cai ZY, Covey DF, et al. Estrogen-like compounds for ischemic neuroprotection. Stroke, 2004; 35(Suppl 1): 2648-2651.

Liu R, Yang SH, Perez E, Vi KD, Wu SS, Eberst K, et al. Neuroprotective effects of a novel non-receptor binding estrogen analogue: In vitro and in vivo analysis. Stroke, 2002; 33: 2485-2491.

Fan T, Yang SH, Johnson E, Osteen B, Hayes R, Day AL, et al. 17β-estradiol can extend ischemic thresholds and exert neuroprotective effects in cerebral subcortex

against transient focal ischemia in rats. Brain Research, 2003; 993:10-17.

He Z, He Y-J, Day AL, Simpkins JW. Proestrus levels of estradiol during transient cerebral ischemia improve histological outcome of the hippocampal CA 1 region:

perfusion-dependent and -independent mechanisms. Journal of the Neurological Sciences, 2002; 193: 79-87.

Yang SH, He Z, Wu SS, He Y-J, Cutright J, Millard WJ, et al. 17 β-estradiol can reduce secondary ischemic damage and mortality of subarachnoid hemorrhage. J Cerebral Blood Flow and Metab, 2001; 21: 174-181.

Yang SH, Liu R, Perez EJ, Wang X, Simpkins JW. Estrogens as protectants of the neurovascular unit against ischemic stroke. Current Drug Targets, 2005a; 4:169-177.

Yang SH, Day AL, Simpkins JW. Estradiol exerts neuroprotective effects when administrated after ischemic insult. Stroke, 2000; 31: 745-749.

Liu R, Wang X, Liu Q, Yang SH, Simpkins JW. Dose dependence and therapeutic window for the neuroprotective effects of 17 β estradiol when administered after cerebral ischemia. Neurosci Lett, 2007; 415(3): 237-241.

Wen Y, Yang SH, Liu R, Brun-Zinkernagel AM, Koulen P, Simpkins JW. Transient cerebral ischemia induces aberrant neuronal cell cycle reentry and Alzheimer’s disease-like tauopathy in female rats. Journal of Biological Chemistry, 2004a; 279: 22684-22692.

Wen Y, Onyewuchi O, Yang SH, Liu R, Simpkins JW. Increased β-secretase activity and expression in rats following transient cerebral ischemia. Brain Research, 2004b; 1009: 1-8.

Wen Y, Yang SH, Liu R, Simpkins JW. Transient cerebral ischemia induces site specific hyperphosphorylation of tau protein. Brain Research, 2004c; 1022: 30-38.

Wen Y, Yang SH, Liu R, Sarkar S, Simpkins JW. Cell-cycle regulators are involved in transient cerebral ischemia induced neuronal apoptosis in female rats. FABS Letters, 2005a; 579: 4591-4599.

Wen Y, Yang SH, Liu R, Perez EJ, Brun-Zinkernagel AM, Koulen P, et al. Cdk5 is involved in NFT-like tauopathy induced by transient cerebral ischemia in female rats. Biochim Biophys Acta, 2007; 1772(4): 473-83.

Yang SH, Liu R, Stevens SM Jr., Valencia T, Wen Y, Brun-Zinkernagel A-M, et al. Mitochondrial localization of estrogen receptor beta. Proc National Academy of

Sciences USA, 2004; 101: 4130-4135.

Yang SH, Sarkar S, Liu R, Yang S, Perez EJ, Wang S, et al. Mitoprotective effects of ERβ knockdown in HT-22 cells. Society for Neuroscience, 2005b; Abstract number


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