Neurotrophic activity

Table 10.12 Molecules displaying neurotrophic activity in vivo and/or with neurons in culture...

Other Cytokines including interleukins 1 (3,2,3,4,5,7,9, 11 and 12 have been reported to exhibit neurotrophic activities [17]. The concentrations of these cytokines in... 

Such an approach could be underpinned by the development of engineered proteins displaying multiple neurotrophic activities. Pan-neurotrophin-1, for example, is an engineered chimaeric neurotrophin, containing the active domains of NGF, BDNF and NT-3. This hybrid molecule can bind the neurotrophin receptors Trk A, B and C, as well as P75. 

Pramipexole is not an ergot derivative, but it has preferential affinity for the D3 family of receptors. It is effective as monotherapy for mild parkinsonism and is also helpful in patients with advanced disease, permitting the dose of levodopa to be reduced and smoothing out response fluctuations. Pramipexole may ameliorate affective symptoms. A possible neuroprotective effect has been suggested by its ability to scavenge hydrogen peroxide and enhance neurotrophic activity in mesencephalic dopaminergic cell cultures. 

Fluoxetine Highly selective blockade of serotonin transporter (SERT) little effect on norepinephrine transporter (NET) Acute increase of serotonergic synaptic activity slower changes in several signaling pathways and neurotrophic activity Major depression, anxiety disorders panic disorder obsessive-compulsive disorder post-traumatic stress disorder perimenopausal vasomotor symptoms eating disorder (bulimia) Half-lives from 15-75 h oral activity Toxicity Well tolerated but cause sexual dysfunction Interactions Some CYP inhibition (fluoxetine 2D6, 3A4 fluvoxamine 1A2 paroxetine 2D6)... 

Another conceivable therapeutic approach for Alzheimer s disease could be based on the administration of neurotrophic factors. Nerve growth factor (NGF) is a 118 amino acid polypeptide with no blood-brain barrier penetrance. Other substances with neurotrophic activity such as epidermal growth factor, brain-derived neurotrophic factor, gangliosides, and the (11-28 peptide of the b-amyloid protein might also have a therapeutic potential. Intracerebroventricular (ICV) administration of NGF has been shown to partially reverse lesion-induced deficits of cortical AChE and choline acetyltransferase (CHAT) activities to promote survival of septal cholinergic neurons after fimbrial transection in adult rats and to reverse behavioral deterioration in rats with such lesions. 

Becerra SR Sagasti A, Spinella R Notario V Pigment epithelium-derived factor behaves like a noninhibitory serpin. Neurotrophic activity does not require the serpin reactive loop. J Biol Chem 1995 270 25992-25999. 

After these pioneering works, several reviews cover the enormous number of papers published in this field [3-7]. The synthesis of oxetanes can have a great importance in the development of compounds with relevant biological properties oxetane ring is present in the skeleton of taxol (1), an important drug used in the treatment of ovarian cancer [8] in merrilactone A (2), a new sesquiterpene dilactone with neurotrophic activity [9] and in several antiviral oxetanes, such as 3, 4, and 5, which have been described in literature (Scheme 3.2) [10-12],... 

Yokoyama, R., Huang, J.M., Yang, C.S. and Fukuyama, Y. (2002) New seco-prezizaane-type sesquiterpenes, jiadifenin with neurotrophic activity and 1,2-dehydroneomajucin from lllicium jiadifengpi. Journal of Natural Products 65(4), 527-531. 

The triazepine dione derivatives 94 (R, R, R, R = H, alkyl groups) have neurotrophic activity and are potentially useful in the treatment and prevention of neuronal disorders including, for example, Parkinson s disease, Alzheimer s disease and multiple sclerosis <03WOP028734>. 

In addition to the neurotrophic activities of FGFs which could be exploited for treatment strategies of the injured CNS, the involvement of FGFs in tumor growth might be also relevant. FGF-2 seems to be a key molecule in glial tumorigenesis.168... 

Tombran-Tink J, Shivaram SM, Chader GJ, Johnson LV, Bok D. 1995. Expression, secretion, and age-related down-regulation of pigment epithelium-derived factor, a serpin with neurotrophic activity. J Neurosci 15 4992-5003. 

Fig. 12.11 Some examples of cyclic FKBP inhibitors that exhibit neurotrophic activity.

Fig. 1. The structure of cyclosporin A (CsA), FK506, rapamycin, and FK506 s derivatives. Note the common structural features of FK506, rapamycin, GPI-1046 and V-10,367, while CsA has an entirely different chemical stracture. Despite their structural differences, CsA and FK506, as immunosuppressants, exhibit a nearly identical spectrum of action on T lymphocytes. In contrast, regardless of their stractural similarity, FK506 and rapamycin exhibit quite different spectra of action on T lymphocytes, though both FK506 and rapamycin are powerful immunosuppressants. GPI-1046 and V-10,367 do not have any immunosuppressive activity however, they have neurotrophic activities as do FK506 and rapamycin.

Besides the immunosuppressive activities, FK506 and CsA have been reported to have neurotrophic activities [9-11]. Although CsA is demonstrated to... 

CHEMISTRY AND NEUROTROPHIC ACTIVITY OF S C0-PREZIZAANE- AND ANISLACTONE-TYPE SESQUITERPENES FROM ILLICIUM SPECIES... 

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