Methamphetamine (METH), the most commonly abused drug, has long been known to induce neurotoxicity. METH causes oxidative stress and inflammation, as well as the overproduction of both reactive oxygen species (ROS) and reactive nitrogen species (RNS). The role of METH-induced brain inflammation remains unclear. Imbroglio activation contributes to the neuronal damage that accompanies injury, disease and inflammation. METH may activate microglia to produce neuroinflammatory molecules. In highly aggressively proliferating immortalized (HAPI) cells, a rat microglial cell line, METH reduced cell viability in a concentration- and time-dependent manner and initiated the expression of interleukin 1beta (IL-1beta), interleukin 6 (IL-6) and tumor necrosis factor alpha. METH also induced the production of both ROS and RNS in microglial cells. Pretreatment with melatonin, a major secretory product of the pineal gland, abolished METH-induced toxicity, suppressed ROS and RNS formation and also had an inhibitory effect on cytotoxic factor gene expression. The expression of cytotoxic factors produced by microglia may contribute to central nervous system degeneration in amphetamine abusers. Melatonin attenuates METH toxicity and inhibits the expression of cytotoxic factor genes associated with ROS and RNS neutralization in HAPI microglia. Thus, melatonin might be one of the neuroprotective agents induced by METH toxicity and/or other immunogens.

The neuroprotective effects of 17 beta -estradiol have been shown in models of central nervous system injury, including ischemia, brain injury, and more recently, spinal cord injury (SCI). Recent epidemiological trends suggest that SCIs in elderly women are increasing; however, the effects of menopause on estrogen-mediated neuroprotection are poorly understood. The objective of this study was to evaluate the effects of 17beta-estradiol and reproductive aging on motor function, neuronal death, and white matter sparing after SCI of post- and pre-menopausal rats. Two-month-old or 1- year-old female rats were ovariectomized and implanted with a silastic capsule containing 180 microg/mL of 17beta-estradiol or vehicle. Complete crush SCI at T8-9 was performed 1 week later. Additional animals of each age group were left ovary-intact but were spinal cord injured. The Basso, Beattie, Bresnahan (BBB) locomotor test was performed. Spinal cords were collected on post-SCI days 1, 7, and 21, and processed for histological markers. Administration of 17beta-estradiol to ovariectomized rats improved recovery of hind-limb locomotion, increased white matter sparing, and decreased apoptosis in both the post- and pre-menopausal rats. Also, ovary-intact 1-year-old rats did worse than ovary-intact 2-month-old rats, suggesting that endogenous estrogen confers neuroprotection in young rats, which is lost in older animals. Taken together, these data suggest that estrogen is neuroprotective in SCI and that the loss of endogenous estrogen-mediated neuroprotective seen in older rats can be attenuated with exogenous administration of 17beta-estradiol.

Several groups have recently shown that 17b-estradiol is protective in spinal cord injury (SCI). Testosterone can be aromatized to 17b-estradiol and may increase estrogen-mediated protection. Alternatively, testosterone has been shown to increase excitotoxicity in models of central nervous system (CNS) injury. These experiments test the hypothesis that endogenous testosterone in male rats alters 17b-estradiol-mediated protection by evaluating a delayed administration over a clinically relevant dose range and manipulating testicular-derived testosterone. Adult male Sprague Dawley rats were either gonadectomized or left gonad-intact prior to SCI. SCI was produced by a midthoracic crush injury. At 30 min post SCI, animals received a subcutaneous pellet of 0.0, 0.05, 0.5, or 5.0 mg of 17b-estradiol, released over 21 days. Hindlimb locomotion was analyzed weekly in the open field. Spinal cords were collected and analyzed for cell death, expression of Bcl-family proteins, and white-matter sparing. Post-SCI administration of the 0.5-or 5.0-mg pellet improved hindlimb locomotion, reduced urinary bladder size, increased neuronal survival, reduced apoptosis, improved the Bax=Bcl-xL protein ratio, and increased white-matter sparing. In the absence of endogenous testicular-derived androgens, SCI induced greater apoptosis, yet 17b-estradiol administration reduced apoptosis to the same extent in gonadectomized and gonadintact male rats. These data suggest that delayed post-SCI administration of a clinically relevant dose of 17b-estradiol is protective in male rats, and endogenous androgens do not alter estrogen-mediated protection. These data suggest that 17b-estradiol is an effective therapeutic intervention for reducing secondary damage after SCI in males, which could be readily translated to clinical trials.

No abstract

In pubertal, but not prepubertal, monkeys ovariectomy (OVX) results in an elevation of circulating luteinizing hormone (LH) levels. To determine if the castration-induced LH increase in pubertal monkeys is due to an increase in pulsatile LH-releasing hormone (LHRH) release, effects of OVX on in vivo LHRH release in the stalk-median eminence were examined in fully conscious monkeys using a push-pull perfusion method. The average ages (+/- SEM) of female rhesus monkeys in each group at OVX were 14.5 +/- 0.6 months (n = 6; prepubertal), 25.0 +/- 1.3 months (n = 5; early pubertal) and 37.8 +/- 2.1 months (n = 6; midpubertal). Perfusate samples from the stalk-median eminence were obtained in 10-min fractions for 6 h in the morning (0600 to 1200 h) and 6 h in the evening (1800 to 2400 h), from the same subjects before OVX, and at 29 days and approximately 100 days after OVX. LHRH levels in perfusates were measured by radioimmunoassay. LH levels throughout the experiment were monitored by periodic blood sampling. OVX resulted in a significant LH increase in early and midpubertal monkeys (P < 0.001 for both), but not in prepubertal monkeys. Similarly, OVX in early and midpubertal monkeys increased mean LHRH release when examined 29 days after surgery (P < 0.05 and P < 0.01, respectively). The OVX-induced LHRH increases in early and midpubertal monkeys remained elevated at approximately 100 days postcastration. Furthermore, it was found that effects of OVX on the increased LHRH release were primarily due to the elevation of basal release and pulse amplitude, but not pulse frequency. In contrast, OVX did not cause any significant effects on pulsatile LHRH release in prepubertal monkeys. The results indicate that an increase in LHRH release and a concomitant increase in circulating LH occurs after OVX in pubertal monkeys, but not in prepubertal monkeys. These data are consistent with the hypothesis that the low level of LH in circulation before the onset of puberty is due to a low amount of LHRH release which is independent of ovarian steroid feedback and that the maturity of the neuronal control system for the pulsatile LHRH release is responsible for the onset of puberty. After the onset of puberty, the negative feedback of ovarian steroid hormones becomes important to the regulation of gonadotropin release.