estradiol-3-benzoate and Nerve-Degeneration

There is a lack of consensus about the effects of the type of menopause (surgical or natural) and of oestrogen replacement therapy on Parkinson's disease. The effects of the timing of replacement therapy and the female's age may explain the observed differences in such effects. However, the mechanisms involved are poorly understood. The renin-angiotensin system mediates the beneficial effects of oestrogen in several tissues, and we have previously shown that dopaminergic cell loss is enhanced by angiotensin via type 1 receptors, which is activated by ageing. In rats, we compared the effects of oestrogen replacement therapy on 6-hydroxydopamine-induced dopaminergic degeneration, nigral renin-angiotensin system activity, activation of the nicotinamide adenine dinucleotide phosphate oxidase complex and levels of the proinflammatory cytokine interleukin-1β in young (surgical) menopausal rats and aged menopausal rats. In young surgically menopausal rats, the renin-angiotensin system activity was higher (i.e. higher angiotensin converting enzyme activity, higher angiotensin type-1 receptor expression and lower angiotensin type-2 receptor expression) than in surgically menopausal rats treated with oestrogen; the nicotinamide adenine dinucleotide phosphate oxidase activity and interleukin-1β expression were also higher in the first group than in the second group. In aged menopausal rats, the levels of nigral renin-angiotensin and nicotinamide adenine dinucleotide phosphate oxidase activity were similar to those observed in surgically menopausal rats. However, oestrogen replacement therapy significantly reduced 6-hydroxydopamine-induced dopaminergic cell loss in young menopausal rats but not in aged rats. Treatment with oestrogen also led to a more marked reduction in nigral renin-angiotensin and nicotinamide adenine dinucleotide phosphate oxidase activity in young surgically menopausal rats (treated either immediately or after a period of hypo-oestrogenicity) than in aged menopausal rats. Interestingly, treatment with the angiotensin type-1 receptor antagonist candesartan led to remarkable reduction in renin-angiotensin system activity and dopaminergic neuron loss in both groups of menopausal rats. This suggests that manipulation of the brain renin-angiotensin system may be an efficient approach for the prevention or treatment of Parkinson's disease in oestrogen-deficient females, together with or instead of oestrogen replacement therapy.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Benzimidazoles; Biphenyl Compounds; Corpus Striatum; Dopaminergic Neurons; Estradiol; Estrogen Replacement Therapy; Female; Nerve Degeneration; Neuroprotective Agents; Ovariectomy; Oxidopamine; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Tetrazoles

MK801, PCP, and ketamine are non-competitive NMDA receptor-antagonists drugs that in humans produce psychomimetic effects and neurocognitive disturbances reminiscent to those of schizophrenia. The administration of these drugs in animals has been used as a pharmacological model to study the NMDA receptor hypofunction-hypothesis of schizophrenia. In animals, the biological effect of MK801 is dose-dependent. Low doses induce behavioral disturbances and higher doses, in addition, promote neurotoxicity in many brain regions, particularly the granular retrosplenial cortex (RSG). The neurotoxic effect of MK801 is sexually dimorphic, being females markedly more sensitive than males; however, the involvement of gonadal hormones is elusive. Here we show that a single intraperitoneal injection of 5 mg/kg of MK801 induced overt neurodegeneration in RSG of female rats, including abundant somatic degeneration in layer 4, and somatodendritic and terminal degeneration in layers 1, 4, and 5. MK801-degeneration in males was scarce and mainly evidenced by the presence of few argirophilic somas in layer 4. Ovariectomized rats were not significantly different than intact females, while orchiectomized rats showed robust MK801-toxicity. Testosterone and dihydrotestosterone (DHT) inhibit MK801-toxicity in orchiectomized rats. In ovariectomized rats only DHT, but not testosterone, prevented MK801-induced degeneration, while in intact females, DHT was only partially protective. Treatment of intact males with estradiol benzoate significantly enhanced MK801-toxicity. Altogether, our experiments indicate that non-aromatizable androgens protect RSG from MK801-toxicity, while estrogens counteract this protection. Thus, the balance of androgens and estrogens delineate the sexual dimorphism of the RSG to the toxic effect of MK801.

Topics: Androgens; Animals; Cell Differentiation; Cerebral Cortex; Contraceptive Agents; Dihydrotestosterone; Dizocilpine Maleate; Estradiol; Excitatory Amino Acid Antagonists; Female; Gonadal Hormones; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Nerve Degeneration; Neurons; Orchiectomy; Ovariectomy; Rats; Rats, Wistar; Sex Factors; Testosterone Propionate

Estrogen increases methamphetamine (MA)-induced neurotoxicity within the impaired nigrostriatal dopaminergic (NSDA) system of ovariectomized female mice, as defined by enhanced striatal dopamine (DA) depletion. In this study we compared the effects of a lower dose of estradiol benzoate (EB, 1 microg) with related agents--tamoxifen (TMX, 12.5 microg), testosterone (5 microg) and dehydroepiandrosterone (DHEA, 3 mg) in this paradigm. In experiment 1, ovariectomized mice received an initial treatment with MA. At 1 week after MA, mice were treated with EB, TMX, testosterone, DHEA or oil vehicle and 24 h later a second MA treatment. Striatal DA and 3,4-dihydroxyphenylacetic acid (DOPAC) concentrations in the MA-treated groups were decreased compared to the non-MA-treated control. Neither EB nor any of the other agents tested showed enhanced neurodegenerative or neuroprotective effects against a second MA invasion. To verify that estrogen was capable of showing a neuroprotective effect under a condition of two administrations of MA, in experiment 2, EB was administered either once or twice prior to each of the two MA treatments. EB treatment prior to the first MA invasion or first and second MA protected the NSDA system against DA and DOPAC depletion. These results imply that a lower dose of EB, TMX, testosterone and DHEA cannot exert neurodegenerative or neuroprotective effects in the impaired NSDA model. However, EB administered prior to the introduction of neurotoxicity can protect the NSDA system. This study may provide an understanding of the variations in results on the effects of estrogen upon the NSDA neurodegenerative disorder, Parkinson's disease.

Topics: 3,4-Dihydroxyphenylacetic Acid; Androgens; Animals; Dopamine; Dopamine Agents; Dose-Response Relationship, Drug; Drug Administration Schedule; Estradiol; Estrogen Antagonists; Female; Methamphetamine; Mice; Neostriatum; Nerve Degeneration; Neuroprotective Agents; Neurotoxins; Ovariectomy; Parkinson Disease; Substantia Nigra; Tamoxifen

The age-related morphological changes in the darkly stained sex-dimorphic nucleus (SDN-POA) and the lighter staining surrounding area (non-SDN-POA) within the medial division of preoptic nucleus of Long-Evans rats were studied. The long-term effects of estradiol benzoate (EB) on the changes were also assessed. During aging, the neuron loss in 14-(middle-age) and 22-month-old rats as well as increased pyknotic ratio of neurons in old male rats were observed in SDN-POA, but not in the non-SDN-POA. In female rats, significant neuron loss with advancing age was observed both in SDN-POA and the non-SDN-POA. Neuron loss in SDN-POA of EB-treated males was more severe than that of the intact males, while no significant difference of neuron loss was observed between EB-treated and age-matched intact female rats. However, neuron loss in SDN-POA of ovariectomized female rats was more severe than that of the age-matched intact females. These results indicate that age-related neuron loss in medial preoptic nucleus show sex-specific and area-specific features, and estradiol may play a important role in modulating neuron loss during aging.

Topics: Aging; Animals; Cell Death; Estradiol; Female; Male; Nerve Degeneration; Neurons; Ovariectomy; Ovary; Preoptic Area; Rats; Sex Characteristics