Neurotrophic Effects

6 Physiological and Pathophysiological Effects of Eicosanoids 5.6.1 Neurotrophic Effects 

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Moore GJ, Hasanat K, Chen G, Seraji-Bozorgzad N, Wilds IB, Faulk MW, Koch S, Jolkovsky L, Manji HK. Lithium Increases N-Acetyl-Aspartate in the Human Brain In Vivo Evidence in Support of bcl-2 s Neurotrophic Effects. Biol Psychiatry 2000 48 1-8. 

IGF-I is widely expressed in the central nervous system. IGF-II is also present, being produced mainly by tissues at vascular interfaces with the brain. Both growth factors, along with insulin, play a number of important roles in the nervous system. They stimulate the growth and development of various neuronal populations and promote neurotrophic effects (discussed later) and may, therefore, be of potential use in the treatment of various neurodegenerative diseases. 

Moore, G.J., Bebchuk, J.M., Hasanat, K., Chen, G., Seraji-Bozorgzad, N., Wilds, I.B., Faulk, M.W., Koch, S., Glitz, D.A., Jolkovsky, L., and Manji, H.K. (2000b) Lithium increases5N-acetyl-aspartate in the human brain in vivo evidence in support of bcl-2 s neurotrophic effects Biol Psychiatry 48 1-8. 

Yuan H, Sarre S, Ebinger G, Michotte Y. Neuropro-tective and neurotrophic effect of apomorphine in the striatal 6-OHDA-lesion rat model of Parkinson s disease. Brain Res. 2004 1026 95-107. 

Klocker, N., Cellerino, A., and Bahr, M. (1998). Free radical scavenging and inhibition of nitric oxide synthase potentiates the neurotrophic effects of brain-derived neurotrophic factor on axotomized retinal ganglion cells in vivo.J. Neurosci. 18, 1038—1046. 

Chen et al. (2000) gave lithium to rats in their chow, achieving blood levels comparable with human treatment, and found a proliferation of brain cells in the hippocampus. They made the leap to claim that this neurotrophic effect may make lithium of use in long-term treatment of other neuropsychiatric disorders. In other words, stimulating the brain to make abnormal brain cells is likely to be good for a variety of psychiatric disorders. This kind of giant leap, utterly ignoring the obvious toxic effects of lithium, has become common in the literature. 

Neurotrophic effects of prolactin on TIDA neuronal development... 

Manji HK, Moore GJ, Chen G. Clinical and preclinical evidence for the neurotrophic effects of mood stabilizers implications for the pathophysiology and treatment of manic-depressive illness. Biol Psychiatry 2000 48(8) 740-54. 

CNTF has also been investigated in mouse models of PD. Although CNTF had potent neurotrophic effects for injured adult rat dopaminergic substantia nigra neurons, it did not prevent the disappearance of the transmitter synthesizing enzyme tyrosine hydroxylase (Hagg and Varon, 1993). Human trials were not conducted. 

Fig. 11 General structure of piperazine phenothiazine derivatives with neuroprotective and/or neurotrophic effects on the central and/or peripheral nervous system...

The manufacture of a phenothiazine-based medicament with neuroprotective and/or neurotrophic effects on the central and/or peripheral nervous system was recently patented [138]. The starting substances were piperazine phenothiazine derivatives, and their pharmaceutically acceptable salts or esters. One of the compounds included in the patent is flufenazine. 

Methyl 3,4-dihydroxybenzoate (MDHB) is a phenolic acid compound, reported to have antioxidative and neurotrophic effects. Pretreatment of primary cortical neurons with MDHB suppressed Ap25 35-induced cellular toxicity and increased the level of Bcl-2, decreased the level of Bax, and inhibited the activation of caspase-9 and caspase-3 [570]. 

Yan, Q., Matheson, C., and Lopez, O. T., In vivo neurotrophic effects of GDNF on neonatal and adult facial motor neurons, Nature, 373, 341, 1995. 

Engele, J. and Bohn, M. C., The neurotrophic effects of fibroblast growth factors on dopaminergic neurons in vitro are mediated by mesencephalic glia, J. Neurosci., 11, 3070, 1991. 

Hou, J.G.G. Lin, L-F.H. Mytilineou, C. Glial cell line derived neurotrophic factor exerts neurotrophic effects on dopaminergic neurons in vitro and promotes their survival and regrowth by 1-methyl 4-pyridinium. J. Neurochem. 1996, 66, 74-82. 

Fiszman ML, Schousboe A (2004) Role of calcium and kinases on the neurotrophic effect induced by gamma-aminobutyric acid. J Neurosci Res 76 435-441. 

However, some molecules have been identified, which induce the synthesis of NGF and potentiate its actions, such as the 5-HT,a receptor agonist SR-57746A (currently in Phase 3 clinical trials), the hypoxanthine AIT-082 (Phase 2) and glycosyl phosphatidylinositol GPI-1046 originally derived from immunophilins (Wood, 1998 see Fig. 1). Disappointingly, an independent analysis of the neurotrophic effects of GPI-1046 (Harper et al., 1999) failed... 

Table 3. In Vitro and In Vivo Neurotrophic Effects of Immunosuppressant Drugs and Their Nonimmunosuppressive...

The results with FK506, rapamycin, and cyclosporin A discussed above indicate that immunophilin ligands possess neuroprotective and neuroregenerative properties, and that both calcineurin-dependent and calcineurin-independent mechanisms are operative. The observation that both FK506 and rapamycin produced neurotrophic effects in vitro suggested that the nerve growth effects of the drugs were mediated, at least in part, by a non-calcineurin mechanism. 

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