Forebrain Cortex Research Articles

Nerve growth factor protects cholinergic neurons against quinolinic acid-induced excitotoxicity in wistar rats

The etiology of neuronal death in neurodegenerative diseases, including Huntington's disease (HD) is still unknown. There could be a complex interplay between altered energy metabolism, excitotoxicity and oxidative stress. Excitotoxic striatal lesions induced by quinolinic acid (QA), were used to test for the neuroprotective actions of nerve growth factor (NGF) on striatal cholinergic and GABAergic neurons. QA is an endogenous excitotoxin acting on N-methyl-D-aspartate (NMDA) receptors, that leads to neurotoxic damage resembling the alterations observed in HD. Unilateral administration of QA, in to the rat striatum in a single dose of 150 nM/L was used as the model of Huntington's disease. The second group was treated both with QA in the same dose and NGF in a dose of 7x10-9 g. NGF was applied immediately before the neurotoxin. The control group was treated with 0.154 mmol/L saline solution likewise. The activity of acetylcholinesterase (AChE) was increased in both the ipsi-and contralateral striatum, forebrain cortex, hippocampus and basal forebrain of QA-treated animals. This was prevented by NGF Some evidence suggests that interaction between neurotrophin receptors and glutamatergic activity may play an important role in plastic changes and synaptic reorganization of striatal circuits after excitotoxic injury. Considering that NGF mediates their activity across glutamatergic synapses and, besides others, also has antioxidative effects, the obtained results indicate its protective role towards functional defects caused by QA.

Effects of various nitric oxide synthase inhibitors on quinolinic acid-induced neuronal injury in rats

The aetiology of neuronal death in neurodegenerative diseases, including Huntington-s disease, is still unknown. There could be a complex interplay among altered energy metabolism, excitotoxicity and oxidative stress. Our aim was to examine the effects of intrastriatal injection of a selective inhibitor of neuronal nitric oxide synthase, 7-nitroindazole, and a non-specific potent nitric oxide synthase inhibitor, Nw-nitro-L-arginine methyl ester, in order to study the possible involvement of glutathione, an important antioxidant, in quinolinic acid-induced striatal toxicity in the rat. Unilateral administration of quinolinic acid to rat striatum in a single dose of 150 nmol/L was used as a model of Huntington-s disease. The other group of animals were pretreated with 7- nitroindazole and Nw-nitro-L-arginine methyl ester, respectively. Control groups were treated with saline solution and olive oil, respectively. Content of total glutathione, was increased in the ipsi- and contralateral striatum, forebrain cortex, basal forebrain and hippocampus in the groups treated with nitric oxid synthase inhibitors and quinolinic acid compared to the quinolinic acid-treated animals. These results support the hypothesis that oxygen free radicals contribute to excitotoxic neuronal injury, and also that nitric oxide synthase inhibitors could be potential neuroprotective agents in Huntington-s disease.

Effects of anabolic steroids and antioxidant vitamins on ethanol-induced tissue injury

Various mechanisms are involved in the process of ethanol-induced tissue impairment. Oxidative stress and its effects are among the most important. We compared the effects of antioxidant vitamins (vitamin C and E in combination) and steroids (testosterone and nandrolone separately) on the toxicity of ethanol in rats. Animals (male Wistar rats, n = 48) were randomised into following groups—Control, Ethanol, Testosterone, Ethanol + Testosterone, Ethanol + Nandrolone, Ethanol + Vitamins. Alcohol was given daily by gavage in a dose of 5 g/kg of body weight. On the 27th day of the study the animals were sacrificed by decapitation and tissue samples were taken. Metabolic status, parameters of the hepatic metabolism, hormone levels (testosterone, ACTH, corticosterone), lipoperoxidation markers (malondialdehyde and conjugated diens in forebrain cortex and in cerebellum) and advanced glycation end-products were analysed. Tissue samples underwent histological examination. Histological outcomes showed a protective effect of antioxidants on hepatic and cerebellar injury caused by chronic ethanol intake. Anabolic steroids protected especially the central nervous tissue against the toxicity of alcohol. Both, antioxidant vitamins and anabolic steroids protect against the ethanol-induced toxicity, however, this effect is tissue specific.

7-Nitroindazole reduces nitrite concentration in rat brain after intrahippocampal kainate-induced seizure

Kainic acid is an endogenous excitotoxin acting on glutamate receptors, that leads to neurotoxic damage resembling the alterations observed in some neurological disorders. Stimulation of glutamate receptors induces neuronal nitric oxide (NO) release, which in turn modulates glutamate transmission. NO may be a key mediator of excitotoxic neuronal injury in the central nervous system. We investigated the effects of 7-nitroindazole, a selective neuronal nitric oxide synthase inhibitor in vivo, on nitrite concentration after kainic acid injection (0.6 mg/ml, pH 7.2) unilaterally into the CA3 region of the rat hippocampus. The accumulation of nitrite, the stable metabolite of NO, was measured by the Griess reaction at different times (5 min, 15 min, 2 h, 48 h and 7 days) following kainate injection in the ipsilateral and contralateral hippocampus, forebrain cortex, striatum and cerebellum homogenates. 7-Nitroindazole (100 μM) can effectively inhibit NO synthesis in rat brain after kainate-induced intrahippocampal neurotoxicity and suppressed nitrite accumulation. The present results suggest that neuronal NO synthase inhibitors may be useful in the treatment of neurological diseases where excitotoxic mechanisms play a role.

Neuron-specific ablation of PDGF-B is compatible with normal central nervous system development and astroglial response to injury.

Members of the PDGF family have multiple roles during embryogenesis and in a variety of pathological situations in the adult. One of the major sites of PDGF-B expression in adult mammals are postmitotic CNS neurons. Combined with reported neurotrophic and neuroprotective effects of exogenously administered PDGFs, this has led to the speculation that PDGF-B may have a role in CNS development, in maintenance, or in response to CNS injury. To test these hypotheses, we developed mice in which PDGF-B was ablated genetically in postmitotic neurons at sites where PDGF-B is normally expressed. We found that these mice develop to adulthood without apparent defects. We demonstrate PDGF-B expression in the postnatal mouse hippocampus and forebrain cortex. We show that neuron-specific knockout of PDGF-B does not influence the astroglial and angiogenic responses to injury in the hippocampus or forebrain cortex. We conclude that the role of neuron-derived PDGF-B remains obscure. A role for neuron-derived PDGF-B, if existing, might be redundant with other CNS growth factors. Alternatively, other and more specific analyses of CNS functions in the normal and injured states will be required to demonstrate such a role.

Nitric oxide (NO) and an NMDA receptor antagonist in pentylenetetrazole-induced convulsions

Controversy about proconvulsant and anticonvulsant nitric oxide (NO) effects and the place of oxidative stress in convulsions, are still a matter of research. We investigated the interaction between 2-amino-5phosphonovaleric acid (APV), a competitive N-methyl-D-aspartate (NMDA) receptor antagonist, and N-nitro-L-arginine methyl ester (LNAME), a nonselective nitric oxide synthase (NOS) antagonist, in pentylenetetrazole (PTZ)-induced convulsions. Pentylenetetrazole was applied to adult Wistar rats intraperitoneally (ip), in a single dose of 80 mg/kg, and L-NAME (10 µg/10 µl) or APV (20 µg/10 µl) intracerebroventricularly (icv), 30 and 10 minutes before PTZ, respectively. In the same manner, another group received both antagonists. Control animals were given 0.9% saline. N-nitro-L-arginine methyl ester exerted a weak anticonvulsant effect, preventing generalized clonic (GCC) and clonic-tonic convulsions (CTC) in 17% of cases. With APV protection against GCC and CTC was 100%, forelimb dystonia (FLD) was decreased in 33% of cases, and time to onset of all convulsive patterns was prolonged (p<0.05 to 0.01). All effects of APV, except in CTC, were reversed by L-NAME applied prior to APV. In APV-PTZ treated animals, superoxide anion content was increased in the forebrain cortex, striatum and hippocampus, without an overwhelmed antioxidative superoxide dismutase (SOD) defence system in the other treatments. When the APV-PTZ group was treated with L-NAME, both SOD activity and superoxide anion content were additionally decreased, indicating that the NOS-NO system was involved in the metabolism of superoxide anions. It is suggested that clinical and biochemical effects of NO strongly depend upon the pretreatment and might lead to a wrong impression of NO contradictory activity.

Nitric oxide synthase inhibitors prevents quinolinic acid-induced neurotoxicity: the role of nitric oxide and glucose-6-phosphate dehydrogenase in cell death

In the present study we employed Nw-nitro-L-arginine methyl ester, non-specific potent nitric oxide synthase inhibitor and a selective inhibitor of neuronal nitric oxide synthase, 7-nitroindazole, reportedly to investigate the possible involvement of nitric oxide in quinolinic acid-induced striatal toxicity in the rat. Quinolinic acid was administered unilaterally into striatum of adult Wistar rats in the single dose of 150 nmol/L. The other two group of animals were pretreated with Nw-nitro-L-arginine methyl ester and 7-nitroindazole respectively. Control groups of animals were treated with 0,154 mmol/L saline solution likewise. Nitrite levels was decreased in the ipsi- and contralateral striatum and forebrain cortex in the group treated with nitric oxide synthase inhibitors and neurotoxin compared to quinolinic acid-treated animals. In the same structures, activity of glucose-6-phosphate dehydrogenase was also decreased, compared to quinolinic acid-treated animals. These results indicate that application of the nitric oxide synthase inhibitors, supressed nitrite accumulation and glucose-6-phosphate dehydrogenase activity and attenuated quinolinic acid-induced neuronal damage in the striatum and forebrain cortex.

Nitric oxide production in the rat brain after kainate-induced seizure

We investigated the role of nitric oxide (NO) as a new neurotransmitter in the control of excitability and neurotoxicity of the hippocampus, forebrain cortex, striatum and cerebellum of the rat, as well as the possible functional interaction between NO and the glutamate system. Kainic acid is an endogenous excitotoxin acting on glutamate non-N-methyl-D-aspartate (non-NMDA) receptors, that leads to neurotoxic damage resembling the alterations observed in some neurological disorders. Stimulation of glutamate receptors induces neuronal NO release, which in turn modulates glutamate transmission. We also investigated the effects of 7-nitroindazole (7-NI), a selective neuronal nitric oxide synthase inhibitor in vivo, on nitrite concentration after kainic acid injection (0.5 mg/ml, pH 7.2) unilaterally into the CA3 region of the rat hippocampus. The accumulation of nitrite, the stable metabolite of NO, was measured by the Griess reaction at different times (5 min, 15 min, 2 h, 48 hand 7 days) following kainate injection in the ipsi- and contralateral hippocampus, forebrain cortex striatum and cerebellum homogenates. 7-NI (WOmicroM) can effectively inhibit NO synthesis in rat brain after kainate-induced intrahippocampal neurotoxicity, suppressed nitrite accumulation and attenuated neuronal damage induced by NMDA overactivity. All data showed that reduction of nitrite levels in the nervous system causes overactivity resulting from the absence of the NO-mediated modulatory action. The relatively transient nitric oxide synthase inhibitory effect of 7-NI following intracerebral injection should be taken into account when using this drug to evaluate the central effects of NO. The present results implicate neuronal NO generation in the pathogenesis of both direct and secondary excitotoxic neuronal injuries in vivo. As such they suggest that neuronal NO synthase inhibitors may be useful in the treatment of neurological diseases in which excitotoxic mechanisms play a role.

Nitric oxide synthase inhibition prevents acute QA-induced neurotoxicity

In the present study we employed 7-NI, reportedly a selective inhibitor of neuronal nitric oxide synthase (NOS) and the non-specific potent NOS inhibitor I-NAME, to investigate the possible involvement of nitric oxide (NO) in quinolinic acid (QA)-induced striatal toxicity in the rat. QA was administered unilaterally into the striatum of adult Wistar rats in the single dose of 150 nmol/L. The second and third group were treated with 7-NI and QA and I-NAME and QA. The control group was treated with O.9% saline solution likewise. Nitrite levels were decreased in the ipsi- and contralateral striatum, forebrain cortex and hippocampus in the group treated with NOS inhibitors (7-NI, I-NAME) and QA compared to QA-treated animals. As 7-NI selectively inhibits the neuronal form of NOS, this study suggests that NO produced from a neuronal and not an epithelial source may contribute to neuronal damage in this model.

Effects of nerve and fibroblast growth factors on the production of nitric oxide in experimental model of Huntington's disease.

The role of nitric oxide (NO) in neurological diseases represents one of the most studied, yet controversial subjects in physiology. The aim was to examine the effects of intrastriatal injection neurotrophins (nerve growth factors-NGF, fibroblast growth factors-FGF) in order to investigate the possible involvement of NO in quinolinic acid (QA) induced striatal toxicity in the rat model of Huntington's disease (HD). QA was administered unilaterally into the striatum of adult Wistar rats in a single dose of 150 nM. The other two groups of animals were pretreated immediately before QA application with NGF and FGF, respectively. Control group was treated with 0.9% saline solution in the same manner. Animals were decapitated 7 days after the treatment. Nitrite levels were significantly decreased both in the ipsi- and contralateral striatum and forebrain cortex of NGF- and FGF-treated animals compared with QA treatment. These results indicated a temporal and spatial propagation of oxidative stress and spread protective effects of NGF and FGF on the forebrain cortex, the distant structure, but tightly connected with striatum, the place of direct neurotoxic damage. Neurotrophins could be the potential neuroprotective agents in HD.

Deafferentation-induced abnormal neurofilament phosphorylation in red nucleus neurones.

Hippocampal deafferentation has been proposed as a pathogenetic mechanism for neurofibrillary tangle (NFT) formation in human mesolimbocortical dementia. We previously developed a rodent model of hippocampal deafferentation involving bilateral destructive lesions of the ventrotegmental area (VTA), septum of the medial forebrain and entorhinal cortex combined with pharmacological inhibition of serotonin 5-HT2 and dopamine D1 receptors. Unexpectedly, we observed an alteration in phosphorylated neurofilament protein immunoreactivity and argyrophilia in magnocellular neurones of the red nucleus. Here, we determined the neuroanatomical, pharmacological and temporal requirements for this effect on red nucleus neurones. We found that abnormal phosphorylation and argyrophilia were critically dependent on bilateral destruction of the VTA and antagonism of 5-HT2 receptors. Although extensive neurofilament hyperphosphorylation and argyrophilia were observed in red nucleus magnocellular neurones within nine days of treatment, no NFTs were formed and these effects were transitory. Resolution of these cytoskeletal abnormalities was accompanied by increased expression of the calcium binding protein, parvalbumin, suggesting that alterations in intraneuronal calcium levels may modify the deafferentation response.

Alzheimer's disease and estrogen

The preventive effect of estrogen on Alzheimer's disease (AD) has become clear with epidemiological data. Therapeutic effects of estrogen have not yet been established. In this presentation, we report our new basic and clinical data. The estrogen receptor, (ER)α, and ERβ mRNA were investigated in rat brain. Estradiol-17β (E 2) treatment following OVX reduced the levels of ERα mRNA in the hypothalamus. In the substantia innominata (SI), the number of choline acetyltransferase immunoreacive cells increased significantly in the estrogen treatment rat. The neurons in SI projecting to the forebrain cortex contained ERα. Increasing amounts of intracellular calcium, peroxidation, and apoptosis with amyloid β were suppressed in neuronal cells from rat pheochromocytoma (PC12) cells with E 2. ERα cDNA transfected PC 12 cells elaborated more neurite-like processes with E 2. In clinics, we are currently preparing vaginal progesterone tablets, which essentially may concentrate in the endometrium to prevent endometrial cancer, with few general circulation of progesterone inviting less depression. The therapeutic effects of cyclic estrogen, such as its preventive effect, are suggested in these studies, at least on mild AD.

Effects of age on elements of insulin-signaling pathway in central nervous system of rats.

Insulin resistance is known to play a pivotal role in type 2 diabetes. Senile individuals, besides being prone to insulin resistance and, consequently, to type 2 diabetes, manifest diseases of the central nervous system (CNS) that may be influenced by disturbances of insulin signaling in the brain, such as memory impairment, Parkinson disease, and Alzheimer disease. We investigated the expression and response to insulin of elements involved in the insulin-signaling pathway in the forebrain cortex and cerebellum of rats ages 1 d to 60 wk. The protein content of insulin receptors and SRC homology adaptor protein (SHC) did not change significantly along the time frame analyzed. However, insulin-induced tyrosine phosphorylation of the insulin receptor and SHC, and the association of SHC/growth factor receptor binding protein-2 (GRB2) decreased significantly from d 1 to wk 60 of life in both types of tissues. Moreover, the expression of SH protein tyrosine phosphatase-2 (SHP2), a tyrosine phosphatase involved in insulin signal transduction and regulation of the insulin signal, decreased significantly with age progression, in both the forebrain cortex and the cerebellum of rats. Thus, elements involved in the insulin-signaling pathway are regulated at the expression and/or functional level in the CNS, and this regulation may play a role in insulin resistance in the brain.

Effects of nitric oxide synthase inhibition on extracellular glutamate and cerebral blood flow during forebrain ischemia-reperfusion in rat in vivo.

To evaluate factors involved in global forebrain ischemia-reperfusion, the effects of the systemically administered NOS inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), on changes in extracellular glutamate and cerebral blood flow (CBF) were studied during the early period of global forebrain ischemia-reperfusion, simultaneously measuring the glutamate released in the rat forebrain cortex and cortical CBF. After injection of saline or L-NAME, forebrain ischemia-reperfusion was performed by bilateral carotid artery occlusion with controlled hemorrhagic hypotension (30 mmHg) for 10 min and reperfusion for 60 min. The microdialysis electrode and laser Doppler flowmetry were used for real-time monitoring of glutamate and CBF, respectively. During ischemia, glutamate increased linearly to over 100 muM and remained elevated 30 min after reperfusion in L-NAME-treated rats. In L-NAME-treated rats, CBF also remained significantly lower than baseline for 30-60 min after reperfusion, and glutamate was higher than in saline-treated rats throughout the experiment. A remarkable linear increase in glutamate release was observed during ischemia. L-NAME did not prevent this dramatic glutamate accumulation, and moreover, its level increased during reperfusion. The decrease in CBF response after reperfusion might be a factor of the elevated glutamate after reperfusion due to a decrease in reuptake of glutamate.

Effects of Hypoxia and Reoxygenation with 21% and 100%-Oxygen on Cerebral Nitric Oxide Concentration and Microcirculation in Newborn Piglets

Bioelectric sensors for continuous registration of nitric oxide (NO) concentrations in tissues provide a new tool for invasive measurement of this gaseous molecule. This study sought to validate cerebral NO measurements using an amperiometric sensor. A series of experiments in 1- to 3-day-old piglets was carried out to study the response of NO and microcirculation during hypoxia (F_iO₂ 0.06) and reoxygenation with 100% and 21% oxygen. Two-channel laser Doppler flowmetry was performed in the forebrain cortex. Significant decreases of NO levels were observed immediately after induction of hypoxemia (p < 0.05). During reoxygenation with 21 or 100% O₂ for 30 min, NO increased significantly compared to the values at the end of hypoxia (p < 0.05). The increase of NO levels in the 100% oxygen group was greater than the increase in the 21% oxygen group (p < 0.05). There were no significant differences between the two groups during the following 3.5 h of observation. A significant increase in CBF was found in the first 2 min of hypoxia (p < 0.05), it then continued to fall to values significantly lower than baseline values at the end of hypoxemia (p < 0.05). During reoxygenation CBF normalised and there were consistent but no significant differences between the two reoxygenation groups. We conclude that NO concentration decreased during the course of hypoxia. Hypoxia-induced cerebral hyperaemia occurred in spite of significantly lower NO concentrations. Reoxygenation with 21 or 100% O₂ restored CBF in both groups similarly, although values were higher after reoxygenation with 100% O₂ compared to air. In fact, reoxygenation with 100% O₂ led to supranormal levels of NO by contrast to 21% O₂.

Thiamine and its derivatives inhibit delayed rectifier potassium channels of rat cultured cortical neurons

We examined the effects of thiamine and its derivatives on voltage-gated ion channels of neuronal cells isolated from fetal forebrain cortex and cultured for 6–14 days. Under the whole-cell voltage clamp, thiamine tetrahydrofurfuryl disulfide (TTFD), a membrane-permeable derivative of thiamine, inhibited the delayed rectifier K + current (I K) in a concentration-dependent manner (10 −4–10 −3 M). The I K-suppressing effect was also observed by internal perfusion with 1 mM thiamine, but not by the external application of thiamine, indicating the poor permeability of thiamine through the cell membrane. However, thiamine which was applied directly to the intracellular side of patch membranes in the inside-out configuration failed to decrease the open probability of the single I K channel. In contrast, thiamine diphosphate decreased both the open probability and the open-time of the channel without changing the single channel conductance. These results suggest that phosphorylated thiamine can function as an endogenous K + channel blocker in neuronal cells. TTFD, when applied extracellularly at a concentration of 1 mM, prolonged the action potential (AP) duration of neurons (172.8±6.6%) without changing the resting membrane potential or AP amplitude, while the same concentration of thiamine did not influence any parameters of the AP, implying that TTFD may cause the potentiation of neuronal AP through the inhibition of I K.

Contraception as prevention and therapy: Sex steroids and the brain

The brain is one of the specific target tissues for sex steroid hormones. Estrogens, progestins and androgens are able to induce several effects in brain areas of the central nervous system (CNS), through the binding with specific receptors. Specific receptors for gonadal steroids have been identified in the amygdala, hippocampus, basal forebrain cortex, cerebellum, locus ceruleus, midbrain rafe nuclei, glial cells, pituitary gland, hypothalamus and central gray matter. At the hypothalamic level, the principal target for sex steroids is those neurons producing the pulsatile release of the gonadotropin releasing hormone (GnRH), localized in the mediobasal hypothalamus and the arcuate nucleus. The GnRH release depends on the complex and co-ordinated interrelationships among gonadal steroids, pituitary gonadotropins and neuroactive transmitters, such as the noradrenaline, dopamine, opioid peptides (β-endorphin), acetylcholine, serotonin, γ-aminobutyrric acid, corticotropin releasing hormone and neuropeptides Y. The interplay of these control mechanisms is governed by peripheral feedback signals; as well as the input from higher brain centers they may modify the GnRH secretion. The anterior pituitary lobe is the best known target tissue for endogenous or exogenous sex steroid hormones, because it is possible to detect luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in blood, as the expression of the pituitary cells' activity. The synthesis and release of FSH and LH by the gonadotropic cells depend upon the peripheral control of gonadal hormones and the GnRH hypothalamic release.In summary, during a woman's reproductive life, the interaction between neurotransmitters, neuropeptides and gonadal hormones modulates the hypothalamo—pituitary—gonadal axis by acting selectively on the synthesis and release of GnRH and of pituitary gonadotropic hormones. The increased use of oral contraceptives in the last 30 years and, in general, of sex steroid hormone derivative therapies, has led to the study of the biochemical and metabolic properties of the different progestin molecules available in hormonal therapies by focusing attention on the interactions between estrogens and progestins in the modulation of the hypothalamo—pituitary-gonadal axis. The different kinds of estrogen and progestin molecules used in oral contraceptives inhibit the ovulatory process and may interfere with other sex steroid hormone receptors, thus exerting multiple effects in each target tissue.

CGP 39653 binding in the chick CNS after NMDA receptor antagonist treatment.

To analyze the affect of blocking neuronal activity on NMDA receptor levels during development, we have injected chick embryos with the competitive NMDA receptor antagonist NPC 12626 from E17 to E19. Brains from drug-treated (n = 7) and control (n = 6) embryos (E20) were processed for receptor autoradiography using the NMDA competitive antagonist [3H]CGP 39653. NPC 12626 treatment caused a significant 24 to 46% increase in [3H]CGP 39653 binding in both the forebrain and cerebellar cortex. The results support the hypothesis that NMDA receptor levels are regulated by activity-dependent mechanisms.

Cyclin I: A New Cyclin Encoded by a Gene Isolated from Human Brain

A new member of the cyclin family has been isolated from an equalized cDNA library derived from human forebrain cortex. This putative cyclin, designated cyclin I, contains a typical cyclin box near the N-terminus and a PEST sequence near the C-terminus. Cyclin I shows the highest sequence similarity in the cyclin box to cyclins G and E, while the similarity between cyclins I and G also extends toward the C-terminus from the cyclin box. Cyclin I mRNA was expressed at high levels in postmitotic tissues, including skeletal muscle, heart, and brain, and was expressed constantly during cell cycle progression. The expression of cyclin I mRNA does not correlate directly to the cell cycle, and therefore cyclin I may be a novel cyclin member that functions independently of the cell cycle control.

Resistance to hypoglycemia of cerebellar transplants in the rat forebrain.

Prolonged insulin-induced hypoglycemia causes widespread loss of neurons and permanent brain damage with irreversible coma. Although the deprivation of carbohydrate stores affects all brain regions, the breakdown of energy metabolism and cessation of protein synthesis occur predominantly in the cerebral cortex, caudoputamen and hippocampus. The cerebellum, brain stem and hypothalamus are largely resistant. Following transplantation of the cerebellar anlage of rat fetuses (day 15 of gestation) into the caudoputamen of adult rats, the grafts were allowed to differentiate for a period of 8 weeks. The host animals were then subjected to 30 min of severe hypoglycemia with isoelectric EEG ('coma'). In contrast to the surrounding vulnerable brain structures, protein synthesis was fully preserved within the cerebellar transplant. Grafting of fetal forebrain cortex to the same location did not result in escape from hypoglycemic cell injury. This indicates that resistance to hypoglycemia is part of the programmed differentiation of the cerebellum and develops irrespective of its location and functional integration within the nervous system.