Protective effects of melatonin and vitamin E in brain damage due to gamma radiation

Gamma radiation is known to cause serious damage in the brain, and many agents have been used for neuroprotection. In this study, lipid peroxidation levels and histopathological changes in brain tissues of whole-body irradiated rats with likely radiation injury were compared to those with melatonin and vitamin E protection. Forty rats in four equal groups were used. The control group received neither radiation nor medication. The remaining groups received doses of 720 cGy in two equal fractions 12 h apart. The second group received radiation but no medication, the third received radiation plus 100 mg/kg per day of vitamin E i.p., and the fourth received radiation plus 100 mg/kg per day of melatonin i.p. over 5 days. On the 10th postoperative day, all the rats were decapitated and specimens from parietal cortices were analyzed for tissue malondialdehyde (MDA) levels and histopathological changes. Increases in MDA were relatively well prevented by melatonin treatment but less so with vitamin E therapy. On histopathological examination, melatonin significantly reduced the rates of edema, necrosis, and neuronal degeneration, whereas vitamin E reduced only necrosis. Neither substance was capable of preventing vasodilatation. In conclusion, melatonin may be useful in preventing the pathological changes of secondary brain damage as a result of free oxygen radicals generated by irradiation.     

Cerebral radioprotection by pentobarbital: dose-response characteristics and association with GABA agonist activity

Pentobarbital reduces cerebral radiation toxicity; however, the mechanism of this phenomenon remains unknown. As an anesthetic and depressant of cerebral metabolism, pentobarbital induces its effects on the central nervous system by stimulating the binding of gamma-aminobutyric acid (GABA) to its receptor and by inhibiting postsynaptic excitatory amino acid activity. The purpose of this study is to investigate the role of these actions as well as other aspects of the radioprotective activity of pentobarbital. Fischer 344 rats were separated into multiple groups and underwent two dose-response evaluations. In one set of experiments to examine the relationship of radioprotection to pentobarbital dose, a range of pentobarbital doses (0 to 75 mg/kg) were given intraperitoneally prior to a constant-level radiation dose (70 Gy). In a second series of experiments to determine the dose-response relationship of radiation protection to radiation dose, a range of radiation doses (10 to 90 Gy) were given with a single pentobarbital dose (60 mg/kg intraperitoneally). Further groups of animals were used to evaluate the importance of the timing of pentobarbital administration, the function of the (+) and (-) isomers of pentobarbital, and the role of an alternative GABA agonist (diazepam). In addition, the potential protective effects of alternative methods of anesthesia (ketamine) and induction of cerebral hypometabolism (hypothermia) were examined. Enhancement of survival time from acute radiation injury due to high-dose single-fraction whole-brain irradiation was maximal with 60 mg/kg of pentobarbital, and occurred over the range of all doses examined between 30 to 90 Gy. Protection was seen only in animals that received the pentobarbital before irradiation. Administration of other compounds that enhance GABA binding (Saffan and diazepam) also significantly enhanced survival time. Ketamine and hypothermia were without protective effect. Protection from acute radiation-induced mortality by pentobarbital in the rat model is a reproducible phenomenon and is associated with the GABA agonistic activity of the compound. This property of GABA agonists offers the potential for a novel approach to enhancement of the efficacy of radiation therapy in the treatment of brain tumors.     

Enhancement of the efficacy of x-irradiation by pentobarbital in a rodent brain-tumor model

Radiation therapy is an important component of brain tumor treatment, but its efficacy is limited by its toxicity to the surrounding normal tissue. Pentobarbital acts as a cerebral radioprotectant, but the selectivity of its protection for the central nervous system has not been demonstrated. To determine if pentobarbital also protects tumor against ionizing radiation, five groups of Fischer 344 rats were observed after exposure to varying combinations of the presence or absence of implanted tumor, pentobarbital, and radiation treatment. The first three groups underwent cerebral implantations of a suspension of 9L gliosarcoma cells. Group 1 was left untreated and served as tumor-bearing controls. Group 2 received 30 Gy of whole-brain x-irradiation without anesthesia 8 days after tumor implantation. Group 3 received the same radiation treatment 15 minutes after pretreatment with 60 mg/kg of pentobarbital intraperitoneally. Groups 4 and 5 served as radiation controls, receiving 30 Gy of x-irradiation while awake and 30 Gy of x-irradiation after pentobarbital administration, respectively. Survival was calculated from the death of the last tumor-bearing rat. The mean survival time in tumor-bearing control rats was 20.8 +/- 2.6 days (+/- standard deviation). X-irradiation alone significantly enhanced the period of survival in rats implanted with the 9L tumor (29.7 +/- 5.6 days, p less than 0.03). Further significant prolongation of survival was seen with the addition of pentobarbital to the treatment regimen (39.9 +/- 13.5 days, p less than 0.01). Nontumor-bearing rats irradiated while awake (Group 4) survived 30.9 +/- 2.3 days. All of their pentobarbital-anesthetized counterparts in Group 5 survived. If pentobarbital had offered radioprotection to the tumor, then Group 3 would have had a shorter survival period than Group 2. This implies that the enhancement of survival time after irradiation results from selective protection of normal brain in this model.     

Malignant astrocytomas: focal tumor recurrence after focal external beam radiation therapy.

Hochberg and Pruitt have reported glioblastomas recurring within 2 cm of the primary site in 90% of patients after whole-brain radiation therapy. They suggested that computerized tomography (CT) scan accuracy would permit smaller radiation fields. A treatment protocol with smaller-field focal brain irradiation following surgical resection is reported. The first 4500 cGy of radiation is focused to within a 3-cm margin around the tumor, with a 1500-cGy boost within a 1.5-cm margin. Forty-two patients with grade III or IV astrocytoma, treated with focal brain radiation therapy were reviewed retrospectively to assess patterns of tumor recurrence. Thirty patients received intra-arterial bromodeoxyuridine (BUdR) radiosensitization with focal brain radiation therapy, and 12 patients underwent conventional focal brain radiation therapy. Tumor margin was defined on preoperative and recurrence CT scans as the contrast-enhanced area; these were traced on acetate templates and compared with each other and with the actual scans. In all 42 patients, the lesion recurred within a 2-cm margin of the original tumor. Four patients had two recurrent areas: the second area was within the 2-cm margin in two, and outside this margin in two. These results are similar to those of Hochberg and Pruitt. It is suggested that focal irradiation is now the optimal treatment for malignant astrocytoma. Since recurrences continue to be within the irradiated volumes, it appears that higher focal doses of radiation are appropriate for clinical treatment trials of malignant astrocytomas.     

Experimental delayed radiation necrosis of the brain. Part 1: Effect of early dexamethasone treatment.

The authors have designed an experiment to detect a hitherto unrecognized interaction between high doses of the glucocorticoid, dexamethasone, and brain irradiation. Eighteen juvenile male rhesus monkeys received 1800 rads to the whole brain in 8.5 minutes. For 1 1/2 days before and 10 1/2 days after the irradiation, nine animals received approximately 2.9 mg/kg/day of dexamethasone intramuscularly in addition to irradiation, while the remaining nine animals served as the control group and received saline. All animals eventually developed a progressive neurological syndrome, and died of delayed radiation necrosis of the brain. The two groups were compared with regard to latency to onset of clinical signs, survival time, and number, distribution, and location of lesions of radionecrosis. Large doses of desamethasone did not alter the susceptibility of the primate brain to delayed radiation necrosis. Detailed morphological study of the radionecrotic lesions supports the hypothesis that most, if not all, of the lesions develop as the consequence of injury to blood vessels.     

Effects of flumazenil on intravenous lidocaine-induced convulsions and anticonvulsant property of diazepam in rats.

We investigated the effect of flumazenil on intravenous (IV) lidocaine-induced convulsions with and without diazepam pretreatment in rats. Wistar rats (200-250 g) were divided into four groups of seven each and were pretreated with IV diazepam or normal saline solution at 6 min and flumazenil or normal saline solution at 3 min before lidocaine infusion. The control group received normal saline solution; the diazepam group received 0.2 mg/kg of diazepam and normal saline solution; the diazepam+flumazenil group received 0.2 mg/kg of diazepam and 0.1 mg/kg of flumazenil; and the flumazenil group received normal saline solution and 0.1 mg/kg of flumazenil. After surgical preparation and recovery from anesthesia, all groups received a continuous IV infusion of lidocaine (15 mg/mL) at a rate of 4 mg.kg-1.min-1 until tonic/clonic convulsions occurred. The values of pH and blood gases were maintained within physiologic ranges. Heart rate was significantly decreased after 5 min of lidocaine infusion, but arterial blood pressure did not change until convulsions occurred in all groups. Pretreatment with diazepam alone increased both cumulative convulsant doses and plasma concentrations of lidocaine at the onset of convulsions. Flumazenil reversed these effects of diazepam. Pretreatment with flumazenil alone changed neither cumulative convulsant doses nor plasma concentrations of lidocaine at the onset of convulsions. Our data show that IV flumazenil reverses the anticonvulsant property of IV diazepam against lidocaine-induced convulsions and that flumazenil itself has no effect on lidocaine-induced convulsions in rats.     

Narcotic dosage and central nervous system opiate receptor binding

Increasing doses of lofentanil (0, 0.08, 0.16, 0.31, 0.63, 1.25, 2.50, 5.00, and 10.0 micrograms/kg), a potent long-acting narcotic, were administered intravenously to rats to examine the relationship among narcotic dosage, degree of analgesia (inhibition of tail withdrawal reflex), anesthesia (no response to bone-crush injury), and central nervous system (CNS) opiate-receptor occupancy (inhibition of [3H] sufentanil binding). Our results demonstrate that increasing doses of lofentanil produce increasing analgesia and anesthesia and eventually complete opiate receptor occupancy. Analgesia occurs with doses of lofentanil (0.31 micrograms/kg) that result in levels of CNS opiate-receptor binding too low to be measured and anesthesia occurs with doses of lofentanil (1.25 micrograms/kg) that produce occupancy of about 25% of the available opiate receptors in subcortical areas and cortex. These findings in rats cannot be applied to narcotic usage in humans, but the data do indicate that in rats a dose eight times the anesthetic dose of lofentanil is needed to saturate virtually all available CNS opiate receptors (10.0 micrograms/kg). Whether saturation of most or all available CNS opiate receptors during narcotic anesthesia is of clinical importance remains to be determined.     

Effect of x-radiation to brain on cerebral glucose utilization in the rat

We assessed, by means of the [14C]-2-deoxy-D-glucose autoradiography method, the effect of whole-brain x-radiation on local cerebral glucose utilization in the rat brain. Animals were exposed to conventional fractionation (200 +/- cGy/day given 5 days a week) to a total dose of 4000 cGy. Metabolic experiments were made 2 weeks after completion of the radiation exposure. In comparison with control and sham-irradiated animals, cerebral metabolic activity was diffusely decreased following irradiation. Statistically significant decreases in metabolic activity were observed in 13 of 27 brain regions studied. In general, brain areas with the highest basal metabolic rates showed the greatest percentage drop of glucose utilization. Post-irradiation metabolic alterations possibly provide an explanation for the syndrome of early delayed deterioration observed in humans after whole-brain radiotherapy.     

Radiobiology of radiosurgery: Part I. The normal rat brain model.

Because limited histological information is available from clinical radiosurgical experience, animal investigations are needed to answer questions regarding the biological response of both normal and pathological tissues. To determine the radiosurgical dose-response relationship of normal brain, we irradiated the right frontal lobe of 18 rats with a single 4-mm isocenter of stereotactic irradiation using the 201-source 60Co gamma unit. Maximal single-fraction doses varied from 30 to 200 Gy (2 rats per dose). All animals were observed for 90 days, killed, and histologically examined. No animal developed neurological dysfunction during that interval, regardless of dose. Animals that received 30, 40, 50, or 60 Gy had no pathological changes. In those given 70 Gy, we found occasional shrunken neurons, and at 80 Gy, rare arteriolar wall thickening. One animal that received 100 Gy had marked capillary endothelial cell degeneration and protein extravasation in the target volume, and the other had a 4-mm diameter necrotic region. Circumscribed cerebral necrosis also was identified in all 4 rats treated with either 150 or 200 Gy; astrocytosis, edema, and microhemorrhage were noted within the surrounding 1 to 2 mm of adjacent brain, and tissue outside that volume had a more normal appearance. We constructed a dose-response relationship based on the cellular, spatial, and temporal effects of focused single-fraction irradiation of the rat brain. To determine the temporal evolution of a known necrotic lesion (200 Gy), 12 other animals were killed (2 each) 1, 7, 14, 21, 30, or 60 days after radiosurgery.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of whole brain radiation on local cerebral glucose utilization in the rat

We assessed, by means of the [14C]-2-deoxy-D-glucose autoradiography method, the effect of whole-brain x-radiation on local cerebral glucose utilization in the rat brain. Animals were exposed to conventional fractionation (200 +/- 4 cGy/day, 5 days/week; total dose, 4000 cGy). Metabolic experiments were made 2 to 3 weeks after completion of the radiation exposure. In comparison with control and sham-irradiated animals, cerebral metabolic activity was diffusely decreased after irradiation. Statistically significant decreases in metabolic activity were observed in 13 of 27 brain regions studied. In general, the brain areas with the highest basal metabolic rates showed the greatest percentage of decrease in glucose utilization. The concept that radiation suppresses glucose utilization before any morphological change takes place in the cell structures was the basis of this study. Metabolic alterations after irradiation may explain the syndrome of early delayed deterioration observed in humans after whole-brain radiotherapy. These studies have applications to observations made with the [18F]-fluorodeoxyglucose method in conjunction with positron emission tomographic scans in patients receiving radiation therapy for intracranial malignancies. The data reported here also have potential clinical implications for the evaluation of a risk/benefit ratio for radiotherapy in patients with benign neurosurgical diseases or children undergoing prophylactic treatment of the central nervous system.     

Primary central nervous system lymphoma

A retrospective analysis of 21 cases of primary central nervous system (CNS) lymphoma is reported. All patients presented with a solitary mass in the supratentorial region. None had previously received immunosuppressive therapy. Neuroradiological studies included technetium-99m-pertechnetate brain scanning in eight cases, cerebral arteriography in all 21 cases, and computerized tomography (CT) in 14 cases. The characteristic features were increased uptake in brain scans, mass effect in arteriograms, and marked contrast enhancement on CT scans. Abnormal tumor vessels were occasionally seen on arteriography, and subtraction films were usually required to appreciate tumor stain. All patients underwent craniotomy, and histological studies of the tumors showed a diffuse type of lymphoma in all cases. Immunoglobulin testing was performed in 19 cases and a monoclonal spike was verified in 10, suggesting a B cell origin. All patients were followed until their death except one who was still alive 12 months from onset of symptoms. Therapy included subtotal resection in all 21 cases, whole-brain irradiation in six cases, chemotherapy in two cases, and a combination of whole-brain irradiation and chemotherapy in nine cases. Three different forms of chemotherapy were used. The results suggest that chemotherapy is an important addition to subtotal resection and whole-brain irradiation in the treatment of primary CNS lymphoma.     

The cerebral radioprotective effect of alternative barbiturates to pentobarbital.

The potential for normal brain tissue injury is one of the limiting factors in the use of radiotherapy for brain tumors. As attempts to enhance brain tumor radiation sensitivity have been unsuccessful, the use of cerebral radioprotectants provides an attractive alternative. Pentobarbital has recently been shown to be a cerebral radioprotectant in the rodent and primate models of single fraction radiation injury. Because daily high doses of pentobarbital bring certain significant risks, the potential usefulness of alternative barbiturates was explored. Seven groups of rats received 70 Gy of whole-brain-only irradiation in the single fraction. Group 1 was treated while awake. Groups 2, 3, and 4 received pentobarbital, thiopental, and methohexital, respectively. Groups 5, 6, and 7 received increasing doses of phenobarbital. Mean group survival at 30 days after treatment was determined and compared with the survival of animals treated while awake. Thiopental enhanced survival, similar to pentobarbital. Methohexital and phenobarbital were of no radioprotective value. The differences in the hypnotic effects of these barbiturates is based on dissimilar effects on the kinetics of chloride ion channel patency. We propose that these differences also influence their radioprotective properties. Thiopental is a shorter acting alternative to pentobarbital for cerebral radioprotection. Use of it should permit safer and easier investigation of this radioprotective effect in human trials.     

Fractionated, single-port radiotherapy delays paresis in a metastatic spinal tumor model in rats

OBJECT: Spinal column metastatic disease affects thousands of cancer patients every year. Radiation therapy frequently represents the primary treatment for this condition. Despite the enormous clinical impact of spinal column metastatic disease, the literature currently lacks an accurate animal model for testing the efficacy of irradiation on spinal column metastases. METHODS: After anesthesia was induced, female Fischer 344 rats underwent a transabdominal approach to the ventral vertebral body (VB) of L-6. A 2- to 3-mm-diameter bur hole was drilled for the implantation of a section of CRL-1666 breast adenocarcinoma. After the animals had recovered from the surgery, they underwent fractionated, single-port radiotherapy beginning on postoperative Day 7. Each group of animals underwent five daily fractions of radiation treatment. Group I animals received a total dose of 10 Gy in 200-cGy daily fractions, Group II animals received a total dose of 20 Gy in 400-cGy daily fractions, and Group III animals received a total dose of 30 Gy in 600-cGy daily fractions. A control group of rats with implanted VB lesions did not receive radiation. To test the effects of radiation toxicity alone, additional rats without implanted tumors received radiation treatments in the same fractions as the rats with tumors. Hindlimb function in all rats was rated before and after radiation treatment using the Basso-Beattie-Bresnahan locomotor rating scale. Histological analysis of spinal cord and vertebral column sections was performed after each animal's death. RESULTS: Functional assessments demonstrated a statistically significant delay in the onset of paresis between the three treatment groups and the control group (tumor implanted but no radiotherapy). The rats in the three treatment groups, however, did not exhibit any significant differences related to hindlimb function. A dose-dependent relationship was found for the percentage of animals who had become paralyzed at the time of death, with all members of the control group and no members of the 30-Gy group exhibiting paralysis. The results of this study do not indicate any overall survival benefit for any level of radiation dose. CONCLUSIONS: These findings demonstrate the efficacy of focal spinal irradiation in delaying the onset of paralysis in a rat metastatic spine tumor model, but without a clear survival benefit. Because of the dose-related toxicity observed in the rats treated with 30 Gy, this effect was most profound for the 20-Gy group. This finding parallels the observed clinical course of spinal column metastatic disease in humans and provides a basis for the future comparison of novel local and systemic treatments to augment the observed effects of focal irradiation.     

Prognosis of primary malignant lymphoma of the central nervous system--a retrospective study of 32 cases.

A retrospective analysis of 32 patients with primary malignant lymphoma of the central nervous system (CNS) diagnosed between 1976 and 1989 investigated treatment results and recurrence patterns. All patients showed either complete or partial regression of the tumor after initial treatment, mainly radiation therapy with adjuvant chemotherapy. The mean dose of whole-brain irradiation was 40.9 Gy and that of booster was 14.4 Gy. Most patients had tumor recurrence. The median time to recurrence from completion of the treatment was 5 months. The 1- and 5-year survival rates were 50.0 and 17.7%, respectively, and the overall median survival time was 11 months. Most tumors had multiple recurrences at the primary site and other regions of the CNS, and tended to recur in the periventricular region and the cerebrospinal fluid space. Spinal metastasis occurred in five cases. The importance of good control of the primary lesion and active maintenance therapy for the whole CNS is emphasized.     

蝇蕈醇和荷苞牡丹碱对大鼠吸入异氟醚时脑环腺苷酸含量变化的影响

目的 观察 GABAA受体激动剂蝇蕈醇和GABAA受体拮抗剂荷苞牡丹碱对大鼠吸入异氟醚时脑cAMP含量变化的影响。方法SD大鼠48只,随机分为对照组,异氟醚组,蝇蕈醇+异氟醚组,荷苞牡丹碱+异氟醚组,蝇蕈醇组和荷苞牡丹碱组。采用cAMP竞争蛋白结合分析法测定大鼠不同脑区cAMP含量。结果 与异氟醚组比较,蝇蕈醇+异氟醚组的翻正反射消失时间明显缩短(P<0.05),而荷苞牡丹碱+异氟醚组却明显延长(P<0.01)。异氟醚组的大脑皮层、脑干的cAMP含量较对照组明显升高(P<0.01)。蝇蕈醇+异氟醚组的大脑皮层、脑干的cAMP含量分别较对照组和异氟醚组升高131％、34％和83％、22％(P<0.05或0.01)。荷苞牡丹碱+异氟醚组的大脑皮层、脑干cAMP含量明显高于对照组,分别较对照组升高41％和60％(P<0.01),其两脑区的cAMP含量与异氟醚组比较却无明显不同。结论 大鼠吸入异氟醚的中枢抑制作用至少部分与GABA能神经元有关。     

Combination of stereotactic radiosurgery and cytokine gene-transduced tumor cell vaccination: a new strategy against metastatic brain tumors.

OBJECT: To determine if the combination of radiosurgery and tumor cell vaccine would enhance the therapy of metastatic lesions of the central nervous system (CNS), the authors examined the antitumoral effects of radiosurgery and cytokine-transduced tumor cell vaccine. METHODS: Fifty-five rats underwent intracranial implantation of 5 x 10(3) MADB 106 cells. On Day 3 after tumor implantation, 34 rats were inoculated in the flank with nonirradiated MADB 106 cells that had been retrovirally transduced to express granulocyte-macrophage colony-stimulating factor or interleukin-4. Twenty-seven rats (17 animals that had received the vaccine and 10 that had not) underwent radiosurgery performed using a gamma knife at maximum doses of 32 Gy on Day 5. No animals in the untreated group or in the vaccine-alone groups survived longer than 21 days. Animals treated by ra diosurgery alone displayed prolonged survival in comparison with untreated animals (p < 0.0001), but only one of 10 animals survived longer than 55 days. In contrast, 14 of 17 animals that received the combination therapy of radiosurgery and vaccination survived longer than 55 days (p = 0.0003 compared with animals that underwent radiosurgery alone). On Day 55, the long-term survivors were challenged by parental MADB 106 cells, which were implanted in the contralateral hemisphere. All animals from the combination therapy groups survived longer than 50 days after this challenge, but the single survivor from the radiosurgery-alone group died of tumor growth in 27 days. CONCLUSIONS: The combination of radiosurgery and cytokine gene-transduced tumor cell vaccine markedly prolonged animal survival and protected animals from a subsequent challenge by parental tumor cells placed in the CNS. The data provided by this study indicate that this combination therapy represents a strategy that may have clinical applicability for single and/or multiple metastatic brain tumors.     

Positron Emission Tomography Study of Regional Cerebral Metabolism in Humans during Isoflurane Anesthesia

Background: Although the anesthetic effects of the intravenous anesthetic agent propofol have been studied in the living human brain using brain imaging technology, the nature of the anesthetic state evident in the human brain during inhalational anesthesia remains unknown. To examine this issue, the authors studied the effects of isoflurane anesthesia on human cerebral glucose metabolism using positron emission tomography (PET).

Methods: Five volunteers each underwent two PET scans; one scan assessed awake-baseline metabolism and the other scan assessed metabolism during isoflurane anesthesia titrated to the point of unresponsiveness (means +/- SD; expired = 0.5 +/- 0.1%). Scans were obtained with a GE2048 scanner (4.5-mm resolution-FWHM) using the18 fluorodeoxyglucose technique.

Results: Awake whole-brain glucose metabolism averaged 6.9 +/- 1.5 mg [center dot] 100 g sup -1 [center dot] min sup -1 (means +/- SD). Isoflurane reduced whole-brain metabolism 46 +/- 11% to 3.6 +/- 0.3 mg [center dot] 100 g sup -1 [center dot] min sup -1 (P less or equal to 0.005). Regional metabolism decreased fairly uniformly throughout the brain, and no evidence of any regional metabolic increases were found in any brain region for any participant. A region-of-interest analysis showed that the pattern of regional metabolism evident during isoflurane anesthesia was not significantly different from that seen when participants were awake.     

Disposition of cerebral metastases from malignant melanoma: implications for radiosurgery

Radiosurgery is becoming more generally available and indications for its use continue to be defined. Cerebral metastases from malignant melanoma are often treated with whole-brain irradiation, but with limited benefit. Innovative treatments, such as radiosurgery, make possible the delivery of doses of radiation that are higher than usual. To determine how many patients might be candidates for radiosurgery, a retrospective analysis of computed tomographic brain scans performed on 41 patients with cerebral metastases from malignant melanoma was undertaken. One-third of these patients were found to have cerebral metastases amenable to a radiosurgical approach, as illustrated radiation dose-volume histograms. Patient and tumor characteristics suggest that this series is represent with cerebral metastases from malignant melanoma. The implications of radiosurgery for normal tissue radiation tolerance and its effects on melanoma are discussed.     

Long-term recovery after bone marrow stromal cell treatment of traumatic brain injury in rats

OBJECT: This study was designed to follow the effects of bone marrow stromal cell (BMSC) administration in rats after traumatic brain injury (TBI) for a 3-month period. METHODS: Forty adult female Wistar rats were injured by a controlled cortical impact and, 1 week later, were injected intravenously with one of three different doses of BMSCs (2 x 10(6), 4 x 10(6), or 8 x 10(6) cells per animal) obtained in male rats. Control rats received phosphate-buffered saline (PBS). Neurological function in these rats was studied using a neurological severity scale (NSS). The rats were killed 3 months after injury, and immunohistochemical stains were applied to brain samples to study the distribution of the BMSCs. Additional brain samples were analyzed by quantitative enzyme-linked immunosorbent assays to measure the expression of the growth factors brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). Three months after injury, BMSCs were present in the injured brain and their number was significantly greater in animals that received 4 x 10(6) or 8 x 10(6) BMSCs than in animals that received 2 x 10(6) BMSCs. The cells were primarily distributed around the lesion boundary zone. Functional outcome was significantly better in rats that received 4 x 10(6) or 8 x 10(6) BMSCs, compared with control animals, although no improvement was seen in animals that received 2 x 10(6) BMSCs. All doses of BMSCs significantly increased the expression of BDNF but not that of NGF; however, this increase was significantly larger in animals that received 4 x 10(6) or 8 x 10(6) BMSCs than in controls or animals that received 2 x 10(6) BMSCs. CONCLUSIONS: In summary, when injected in rats after TBI, BMSCs are present in the brain 3 months later and significantly improve functional outcome.     

Effective antitumor immunity following elimination of suppressor T cell function.

An increased resistance to a transplantable tumor was demonstrable in Fischer (F344) strain rats after thymectomy and high doses of total body irradiation, followed by bone marrow cell repopulation if the animals were allowed to recover for 6 to 8 weeks. Further experiments demonstrated that removal of a subpopulation of T cells by lower doses of radiation plus thymectomy could (1) reduce recurrences after surgical excision, and (2) prolong survival of animals with established pulmonary metastases. It was found that thymectomy + 50 leads to 100 R total body irradiation could eliminate a T cell-mediated suppression of effective antitumor immunity. The removal of the suppressor cell component by lower doses of irradiation was dependent on pre-exposure of the animals to tumor antigen. These experiments indicate the specificity of suppressor T cells to tumor antigen and their exquisite sensitivity to radiation in appropriate circumstances.