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PubMed1995

Lipid peroxidation inhibits acyl-CoA:-1-acyl-sn-glycero-3-phosphocholine O-acyltransferase but not CTP: phosphocholine cytidylyltransferase activity in rat brain membranes.

In brain tissue in vivo peroxidized according to three model systems, we determined two microsomal enzyme activities involved in phospholipid biosynthesis. The first, short-term model, was based on the i.v. administration to normal rats, twice a day, for a period of 1 week, of a sonicated emulsion of a peroxidized mixture of phospholipids and linoleate (4:1, w/w; 500 mg/day; hydroperoxides: 200-250 nmol/mg lipid). The half-life time of the injected toxic lipid species in the blood circulation was about 1 h. At the end of the week's treatment, brain and liver malondialdehyde, conjugated diene and lipid hydroperoxide levels were significantly higher in treated rats than in the controls. The second model consisted of the acute injection of aqueous Fe2+ solution (50 mM) into lateral ventricles, and the collection of brain tissue 2 h later. The third model was based on two consecutive injections of hydroperoxylinoleate (1 mg each) into lateral ventricles over a period of 18 h, and the collection of brain tissue 2 h after the second administration. In brain microsomal membranes prepared from peroxide- or iron-treated rats, lysophosphatidylcholine acyltransferase activity exhibited a significant inhibition. On the contrary, in microsomal preparations derived from the short-term model, CTP:phosphocholine cytidylyltransferase activity was slightly stimulated. Intraventricular injection of linoleate or linoleic acid hydroperoxide left this enzyme activity unchanged. The effect of in vitro membrane peroxidation on both microsomal enzyme activities was investigated. By using an Fe2+ (20 microM)-ascorbate (0.25 mM) peroxidation system, the residual acyltransferase and cytidylyltransferase activities were 80 and 72% of initial activity respectively. Significant dose-dependent inactivation of acyltransferase (maximum loss of 45% of initial activity) was seen when 0.1-10 mumol of photooxidized phospholipids were preincubated with 100 micrograms of microsomal membranes. Unoxidized or photooxidized phospholipids (1 mM) promoted a slight stimulation of cytidylyltransferase activity. Altogether, the results suggest a link between oxygen radical generation and the perturbation of the membrane structure in which the enzymes are located.

1-Acylglycerophosphocholine O-Acyltransferase↗
PubMed1972

Effects of muscarine given into the brain of fowls.

1. The effects of muscarine, given intraventricularly, in adult conscious fowls (Gallus domesticus) or microinfused into various brain regions of conscious young chicks, were tested on behaviour, electrocortical activity and respiratory rate. Its effects given intraventricularly or intravenously to anaesthetized fowls were also examined.2. After intraventricular injection, muscarine elicited immediate behavioural and electrocortical arousal; body temperature was unaffected. After a delay of 30-40 min, tachypnoea developed together with postural changes which included partial abduction of the wings away from the trunk, the back and tail becoming horizontal. These effects were prevented by intravenous or intraperitoneal atropine or hyoscine, but not by pempidine or methylatropine, and were potentiated by physostigmine. Hyoscine given intraventricularly or intravenously did not affect electrocortical activity.3. Intraventricular muscarine given to anaesthetized adult fowls produced brief apnoea. On return of respiration, amplitude of respiratory excursion was diminished for about 5 min; tachypnoea did not develop. Blood pressure also rose briefly. With larger doses of intraventricular muscarine, large amplitude electromyographic potentials developed in the dorsal neck muscles followed later by side-to-side neck movements.4. Muscarine given intravenously to anaesthetized adult fowls, raised blood pressure and perfusion pressure in a perfused hind limb, an effect most likely due to secretion of adrenal medullary catecholamines; these pressor effects were prevented by pempidine and phenoxybenzamine. Given directly to the perfused hind limb, muscarine lowered perfusion pressure.5. In young chicks, muscarine microinfused into the diencephalon or myelencephalon elicited intense bilateral electrocortical alerting associated with periods of alternating violent motor activity and quiescence. Microinfusion of muscarine into the telencephalon induced ipsilateral electrocortical desynchronization without affecting behaviour. These effects of muscarine were prevented by intravenous, intraperitoneal or intracerebral hyoscine, but once its effects were established could be antagonized only with difficulty; pempidine did not prevent these effects. Microinfusions of muscarine into the brain did not affect posture, respiration or temperature.

Alkaloids↗
PubMed1977

beta-Endorphin: endogenous opiate or neuroleptic?

The opiatelike neuropeptide beta-endorphin produces a spectrum of effects that contrasts with that induced by the neuroleptic haloperidol. Rats injected intraventricularly or directly into the periaqueductal gray with beta-endorphin (0.5 to 50 micrograms) exhibited rigid immobility accompanied by the loss of righting reflex; the period of rigidity was preceded or followed (depending upon dose) by a state of hyperactivity. In contrast, no dose of haloperidol tested (0.5 to 12 milligrams per kilogram) produced rigidity, loss of righting reflex, or behavioral excitation. Furthermore, whereas animals injected with haloperidol remained stationary on a vertical grid, rats injected with beta-endorphin typically slid off the grid. Moreover, combined beta-endorphin and haloperidol treatment produced flaccidity in most animals. These results do not support the contention that this opiatelike peptide may be a naturally occurring neuroleptic.

Animals↗
PubMed1997

Intraventricular immunotoxin therapy for leptomeningeal neoplasia.

OBJECTIVE: The goals of this clinical trial of intraventricular 454A12-rRA therapy were to identify dose-limiting toxicities, to evaluate the pharmacokinetics of single-dose intraventricular 454A12-rRA, and to detect antitumor activity. METHODS: We performed a pilot study of intraventricular therapy with the immunotoxin 454A12-rRA in eight patients with leptomeningeal spread of systemic neoplasia. The immunotoxin 454A12-rRA is a conjugate of a monoclonal antibody against the human transferrin receptor and recombinant ricin A chain, the enzymatically active subunit of the protein toxin ricin. Patients were treated with single doses of 454A12-rRA ranging from 1.2 to 1200 micrograms. RESULTS: The early phase half-life of 454A12-rRA in ventricular cerebrospinal fluid (CSF) averaged 44 +/- 21 minutes, and the late phase half-life averaged 237 +/- 86 minutes. The clearance of the immunotoxin was faster than the clearance of coinjected technetium-99m-diethylenetriamine penta-acetic acid, averaging approximately 2.4-fold greater. No 454A12-rRA degradation was detected by Western blot analysis of ventricular CSF for a period of 24 hours, and bioactivity was retained in CSF paralleling the concentration of immunotoxin. No acute or chronic drug toxicity was identified in patients who received less than or equal to 38 micrograms of 454A12-rRA by intraventricular injection. Doses more than or equal to 120 micrograms caused a CSF inflammatory response that was associated with transient headache, vomiting, and altered mental status. This acute syndrome was responsive to steroids and CSF drainage. No systemic toxicity was detected. In four of the eight patients, a greater than 50% reduction of tumor cell counts in the lumbar CSF occurred within 5 to 7 days after the intraventricular dose of 454A12-rRA; however, no patient had their CSF cleared of tumor, and clinical or magnetic resonance imaging evidence of tumor progression was demonstrated in seven of the eight patients after treatment. CONCLUSION: Tumoricidal concentrations of the immunotoxin 454A12-rRA can be attained safely in the CSF of patients with leptomeningeal tumor spread.

Adult↗
PubMed1977

Independent receptors for pressor and drinking responses to central injections of angiotensin II and carbachol.

Angiotensin II and carbachol when injected in the brain ventricles of the rat produce similar responses of an increase in blood pressure and drinking behavior. The question of whether these effects are produced by independent receptors or via a cholinergic circuit is debatable for the drinking behavior and evidence is lacking for the blood pressure effect. We have used a chronic rat preparation for recording blood pressure and drinking at the same time during intraventricular injections (i.v.t.) of both angiotensin and carbachol and i.v.t. or intravenous infusions of appropriate antagonists. The results show that drinking and blood pressure response to angiotensin II can be blocked by P113 (500 ng 1.v.t.) an angiotensin antagonist; they are not blocked by atropine (10 mug i.v.t.) a cholinergic antagonist; carbachol effects, however, are not blocked by P113, but are totally blocked by atropine (10 mug i.v.t.), At high doses of atropine there is inhibition of both agents but this probably represents a general inhibition. The hormone and cholinomimetic administered together interact and both are inhibited by adrenergic stimulation. We conclude from these experiments that angiotensin and carbachol act upon independent receptors in the brain to produce blood pressure and drinking responses but at some point they share common, central effector pathways.

Angiotensin II↗
PubMed1996

Selective immunolesioning of the basal forebrain cholinergic system disrupts short-term memory in rats.

Selective depletion of nerve growth factor receptor-bearing neurons in the basal forebrain cholinergic system nuclei by the immunotoxin 192 IgG-saporin offers a new and highly useful tool for the study of the role of the forebrain cholinergic system in cognitive functions. In the present study, we have tested the effects of 192 IpG-saporin in an operant delayed matching-to-position task which has previously been used to discriminate between delay-dependent learning impairments and delay-independent disturbances of non-mnemonic processes. Rats were first trained to criterion performance and then received intraventricular injections of 5 microg of 192 IgG-saporin 4 weeks prior to a second testing session. Rats with 192 IgG-saporin lesions displayed a significant delay-dependent decline in performance compared to normal controls, indicating a deficit in short-term memory. Administration of the muscarinic blocker scopolamine (0.5 mg/kg, i.p.) produced more pronounced impairment in the performance of the normal control rats across all delays, and induced further impairment also in animals with 192 IgG-saporin lesions. These effects were not observed following control injections of methyl scopolamine, suggesting that the impairment induced by scopolamine was due to the blockade of central muscarinic receptors. No improvement in performance was observed in either group following systemic treatment with the muscarinic cholinergic agonist arecoline (1.00 mg/kg). Biochemical and morphological analyses confirmed the selective and severe (>90-95%) depletion of cholinergic neurons throughout the septal-diagonal band area and the nucleus basalis region by the intraventricular 192 IgG-saporin treatment. Although the immunotoxin was observed to produce additional damage to the cerebellar Purkinje cells, no gross motor abnormalities were observed that could contribute to the effects on accuracy in the task used here. In conclusion, the results show that selective combined lesions of the basal forebrain cholinergic neurons in the septal-diagonal band area and nucleus basalis produce long-lasting impairments in short-term memory, thus providing further support for a role of this system in cognitive functions.

Animals↗
PubMed1991

Molecular base of acetylcholine and morphine analgesia.

We have previously described the peripheral analgesic effect of dibutyryl cyclic GMP, acetylcholine (ACh) and morphine (Mph) injected into the rat paws. Since ACh induces nitric oxide (NO) release from endothelial cells which is though to stimulate guanylate cyclase (GC) we investigated if NO-cyclic GMP pathway was involved in the analgesia by those agents. Using a modification of the Randall-Selitto rat paw test, it was found that sodium nitroprusside, which releases NO non-enzymatically, blocked rat paw PGE2 induced hyperalgesia. The peripheral analgesic effect of sodium nitroprusside, ACh and morphine was enhanced by intraplantar injection of an inhibitor of cyclic GMP phosphodiesterase (MY5445) and blocked by a GC inhibitor, methylene blue (MB). Peripheral analgesia induced by ACh and morphine, but not by sodium nitroprusside, was blocked by NG-monomethyl-L-arginine (L-NMMA) an inhibitor of the formation of NO from L-arginine. Central effect of morphine as tested by the rat paw and by the tail flick tests was inhibited by intraventricular injection of methylene blue. In addition, the central morphine analgesia was potentiated by My5445. In contrast, with the periphery, the central effect of morphine was not blocked by L-NMMA. Our results demonstrate that NO causes peripheral analgesia via stimulation of GC and supports the suggestion that at this site morphine and acetylcholine analgesia is subsequent to NO release. In the mechanism of the central analgesic effect of morphine, the cGMP system is activated but via NO release, probably by a direct stimulation of the receptors. This is the first demonstration that links peripheral and central analgesic effect of morphine to the stimulation of GC system.

Acetylcholine↗
PubMed1984

The effect and possible mode of action of alpha-melanocyte-stimulating hormone on gonadotropin release in the ovariectomized rat: an in vivo and in vitro analysis.

This study was designed to examine the possible effects of alpha MSH on gonadotropin release. Injection of alpha MSH into the third ventricle of the brain and sampling at 5, 10, 15, 30, and 60 min postinjection produced a significant lowering of plasma LH, but not of FSH, in conscious ovariectomized (OVX) rats. The minimum effective dose was 1 microgram. This procedure did not affect plasma levels of LH or FSH in estradiol benzoate-primed, OVX rats. Multiple blood sampling every 10 min before and after intraventricular injection of alpha MSH (2 micrograms) produced a significant reduction in the area under the secretion curve of LH. Intravenous injection of alpha MSH had little effect; however, a slight lowering of plasma LH occurred in OVX rats after a 50-micrograms dose. The effect of alpha MSH on LH release was blocked by pretreatment of the animals with alpha-methyl-paratyrosine, an inhibitor of catecholamine synthesis, as well as by pretreatment with an iv injection of spiroperidol, a dopamine receptor blocker. The peptide failed to alter basal or K+-stimulated LHRH release from median eminence fragments of OVX rats incubated in vitro. Alpha MSH had no effect on LHRH-induced LH release in vivo and failed to alter the release of FSH and LH from hemipituitaries of OVX rats or dispersed cells from OVX, estradiol benzoate-primed rats in vitro. It is concluded that alpha MSH exerts an inhibitory effect on LH release by an action on the hypothalamus, probably via activation of the tuberoinfundibular dopaminergic system.

Animals↗
PubMed1981

Modification of environmentally cued tolerance to ethanol in mice.

Tolerance to the hypnotic and hypothermic effects of ethanol in mice develops with multiple injections. The tolerance to both of these effects of ethanol can be reduced by testing the animals in a novel environment, suggesting that the tolerance may be learned. Tolerance to the hypothermic effect of ethanol develops more rapidly than tolerance to the hypnotic effect. Disruption of the brain catecholamine systems, with either 6-hydroxydopamine or alpha-methyl-p-tyrosine slows the rate of development of tolerance to the hypnotic effect of ethanol. Intraventricular injection of the serotonergic neurotoxin 5,7-dihydroxytryptamine, increases initial sensitivity to ethanol-induced narcosis and facilitates the development of tolerance to the hypnotic effects of ethanol. Tolerance to the hypothermic effect of ethanol in a familiar environment is unaffected by either of the neurotoxins or by alpha-methyl-p-tyrosine. However, initial sensitivity to the temperature-lowering effect of ethanol is increased by 6-hydroxydopamine and decreased by alpha-methyl-p-tyrosine administration. Learning may be an important factor in development of tolerance to ethanol under some conditions and tolerance produced under these conditions can be modified by disruption of central catecholamine systems.

5,7-Dihydroxytryptamine↗
PubMedDate not supplied

Significant entry of tubocurarine into the brain of rats by adsorption to polysorbate 80-coated polybutylcyanoacrylate nanoparticles: an in situ brain perfusion study.

The possibility of using polysorbate 80-coated polybutylcyanoacrylate nanoparticles to deliver low molecular polar hydrophilic drugs to the CNS has been studied. Tubocurarine (a quaternary ammonium salt) does not penetrate the normal intact blood-brain barrier. However, the injection of this drug directly into the cerebral ventricles of the brain provokes the development of epileptiform seizures as assessed by electroencephalogram (EEG). An in situ perfused rat brain technique was used as an experimental technique together with a simultaneous recording of the EEG. Nanoparticles were prepared by butylcyanoacrylate polymerization in an acidic medium. Fifteen minutes after the introduction of tubocurarine-loaded polysorbate 80-coated nanoparticles into the perfusate, epileptiform spikes in the EEG appeared. Intraventricular injection of tubocurarine caused the appearance of the EEG seizures 5 min after administration. Neither tubocurarine solution nor tubocurarine-loaded nanoparticles without polysorbate 80 or a mixture of polysorbate 80 and tubocurarine were able to influence the EEG. Thus only the loading of tubocurarine onto the polysorbate 80-coated nanoparticles appears to enable the transport of this quaternary ammonium compound through the blood-brain barrier.

Adsorption↗
PubMed1993

The role of iron in senescence of dopaminergic neurons in Parkinson's disease.

In Parkinson's disease (PD) an elevation of iron with staging of the disease has been observed in the substantia nigra (SN), especially the zona compacta (ZC). The iron is found to be present in glia, active microglia, macrophages, oligodendrocytes, outside the degenerated dopamine neurons and as a mild halo around Lewy bodies and within melanized dopamine neurons of SNZC. Although in control brains iron is absent in melanized dopamine neurons, in PD it is bound to neuromelanin in a fashion similar to the interaction of iron with synthetic dopamine-melanin. The iron in SNZC is thought to induce oxidative stress and thus be associated with the reported decreases of glutathione peroxidase activity, reduced glutathione (GSH), mitochondrial Complex I activity, calcium binding protein and increase of basal lipid peroxidation. An animal (rat) model of PD has been described in which intranigral iron injection induces a relatively specific lesioning of dopamine neurons resulting in behavioural and biochemical Parkinsonism in rats. Support for the neurotoxicity of iron liberated from an endogenous source has come from the 6-hydroxydopamine model of PD. This neurotoxin is thought to owe its toxicity to the liberation of iron from ferritin, which in turn alters the homeostasis of mitochondrial Ca2+ with the subsequent depletion of tissue GSH, resulting in oxidative stress. Pretreatment of rats with intraventricular injection of a relatively selective prototype iron chelator, desferrioxamine (desferal), attenuates the 6-hydroxydopamine lesion of nigrostriatal dopamine. Thus iron can fulfill the role of a neurotoxin. However it remains to be established whether its role in PD is primary or secondary to some other neurotoxic event.

Aging↗
PubMed1982

Relationship between prolactin in the serum and cerebrospinal fluid of ovariectomized female rhesus monkeys.

The entry of prolactin into the cerebrospinal fluid from the blood, and the relation between levels in the two compartments were studied under a variety of conditions in ovariectomized rhesus monkeys. Prolonged treatment with either domperidone or sulpiride, both dopamine-receptor blockers, elevated prolactin levels in serum and cerebrospinal fluid proportionally equally, so that the cerebrospinal fluid serum ratio was unchanged from controls (circa 12-20%). Gel filtration showed that only 'little' (monomeric) prolactin entered the cerebrospinal fluid in such monkeys. Following acute elevations of blood prolactin after a single injection of either sulpiride or ovine prolactin, cerebrospinal fluid levels increased linearly over a 90 min sampling period, despite falling serum levels. The rate of entry of prolactin into the cerebrospinal fluid was similar after either procedure, and was independent of absolute serum or cerebrospinal fluid levels, suggesting a rate-limiting mechanism. Furthermore, retrograde portal blood flow from the pituitary is not necessary to account for these results. Clearance of prolactin from the third ventricle was studied following intraventricular injection of prolactin. Prolactin was removed from the cerebrospinal fluid by a mechanism whose efficiency compares with that in serum, so that the half-life of prolactin in either compartment is about the same. Measurement of sodium, potassium and calcium in the cerebrospinal fluid during prolonged hyperprolactinaemia showed no change, indicating that the central effects of prolactin are not due to alteration of these electrolytes. These results show that cerebrospinal fluid levels of prolactin, and hence, those surrounding the brain, can be inferred accurately from those in the blood, and suggest that there may be a selective mechanism regulating the entry of prolactin into the cerebral compartment.

Animals↗
PubMed1984

Inhibition by gastrin-releasing peptide of growth hormone (GH) secretion induced by human pancreatic GH-releasing factor in rats.

Intravenous injection of synthetic human pancreatic GH-releasing factor (1-44) [hpGRF(1-44)] (50 ng-1 micrograms/100 g BW) resulted in a dose-related increase in plasma GH levels in urethane-anesthetized male rats. Pretreatment with cysteamine (30 mg/100 g BW, sc, 4 h previously) or anti-SRIF rabbit serum (0.5 ml/rat, iv, 1 h previously) raised basal plasma GH levels and markedly exaggerated the plasma GH response to hpGRF (1-44) (80 ng/100 g BW, iv). The intraventricular injection of gastrin-releasing peptide (GRP) (1 micrograms/rat) completely inhibited the increase of plasma GH induced by hpGRF (80 ng/100 g BW, iv) in control rats. However, in the rats treated with cysteamine or anti-SRIF rabbit serum, the inhibitory effect of GRP on hpGRF-induced GH release was significantly attenuated. hpGRF (10(-11)-10(-8) M) stimulated in a dose-related manner GH release from rat anterior pituitary cells superfused in vitro. GRP (10(-5) M) did not affect pituitary GH release induced by hpGRF (10(-9) M) in vitro. These results indicate that hpGRF stimulates rat GH secretion by acting at the pituitary level and the hypothalamic SRIF interacts with the action of GRF, and that GRP inhibits GH secretion, at least in part, by stimulating SRIF release from the hypothalamus.

Animals↗
PubMed1998

Importance of neurokinin-1 receptors in the nucleus tractus solitarii of mice for the integration of cardiac vagal inputs.

Unmyelinated vagal afferents from the heart terminate within the nucleus tractus solitarii (NTS) located in the dorsomedial medulla. The neurotransmitter and postsynaptic receptors mediating information from cardiac vagal receptors to the NTS are unknown. This study determined the effects of neurokinin-1 (NK1) receptor blockade on: (i) the reflex response evoked following aortic root injection of either veratridine (1-3 microg/kg) or bradykinin (80-300 ng/kg) to stimulate cardiac receptors in in vivo anaesthetized mice; and (ii) the evoked synaptic response of cardioreceptive NTS neurons following both intraleft-ventricular injection of veratridine or bradykinin, and electrical stimulation of the ipsilateral vagus nerve in an arterially perfused working heart-brainstem preparation of mouse. Administration of CP-99,994 (0.75-1.5 mg/kg i.v.), a specific NK1 antagonist, attenuated significantly the evoked reflex bradycardia and depressor response following cardiac receptor (n = 6), but not pulmonary chemoreflex stimulation in vivo. From extracellular recordings of cardioreceptive NTS neurons, CP-99,994 reduced reversibly the total number of evoked spikes, peak firing frequency and response duration evoked by intraventricular injections of veratridine (n = 5) or bradykinin (n = 5). The number of evoked action potentials following electrical stimulation of the vagus nerve was also reduced. In five whole cell recordings of NTS neurons, both the evoked depolarization following cardiac receptor stimulation, and the peak amplitude and duration of vagus nerve-evoked EPSPs were reduced by CP-99,994; synaptic inputs from both peripheral chemoreceptors or pulmonary C-fibres were unaffected. These data support a selective involvement of NK1 receptors in the transmission of cardiac vagal afferent inputs to NTS neurons integrating cardiorespiratory information.

Afferent Pathways↗
PubMed1978

D-Proline: stereospecificity and sodium chloride dependence of lethal convulsant activity in the chick.

Two- and five-day old chicks were injected intraventricularly with D-proline and structurally related compounds. D-proline produced convulsions and lethality, but was non-amnestic, whereas the naturally-occurring isomer, L-proline, was non-convulsant and non-toxic but amnestic. D-proline convulsions were accompanied by decreased high frequency in the EEG and increased slow wave activity. High amplitude spiking was not observed. The lethality of D-proline was saline-dependent. Control experiments ruled out possible toxic factors such as hypertonicity, pH pyrogens, injection volume, or needle misplacement. The results demonstrate that saline and distilled water are not equivalent injection vehicles. A sodium-free vehicle may lead to artifacts but is advantageous in experiments in which amino acid transport must be minimized.

Animals↗
PubMed1989

Expression of c-Fos immunoreactivity in transmitter-characterized neurons after stress.

The effect of intracerebroventricular injection of the mitosis inhibitor colchicine and of immobilization stress, subcutaneous injection of capsaicin, and intraperitoneal injection of hypertonic salt solution on expression of c-Fos-like immunoreactivity was studied in the rat brain with immunohistochemistry. All the procedures induced c-Fos immunoreactivity in parvocellular neurons of the paraventricular nucleus, and many of these neurons also contained corticotropin-releasing factor immunoreactivity. c-Fos immunoreactivity was also observed, for example, in subpopulations of neurons in the locus coeruleus, the ventrolateral medulla oblongata, and the nucleus tractus solitarii. Many of these cells also expressed catecholamine-synthesizing enzymes. The results suggest that intraventricular injection of colchicine is a stressful stimulus and support the view that several catecholamine cell groups in the lower brainstem are part of the brain circuitry mediating stress reactions, as are the hypothalamic neurons that contain corticotropin-releasing factor.

Animals↗
PubMed1995

Regional incorporation and site-specific differentiation of striatal precursors transplanted to the embryonic forebrain ventricle.

The developmental potential of neural progenitors derived from the E13.5-E14 lateral or medial ganglionic eminences (LGE and MGE, respectively) or the E12 ventral mesencephalon (VM) was examined in cross-species transplantation model. After injection into the E15 rat forebrain ventricle, mouse LGE progenitors (unlike those of the MGE or VM) were consistently integrated into the host striatum, expressing neurochemical phenotypes and axonal projections characteristic of striatal projection neurons. Additionally, both LGE and MGE precursors displayed widespread incorporation into distinct forebrain and midbrain structures, whereas the more caudally derived VM cells were largely confined to midbrain structures. These results suggest that many LGE precursors are positionally specified for striatal incorporation, while a portion also possess greater potential reflected in more widespread integration following intraventricular injection.

Animals↗
PubMed2003

Endogenous and exogenous ciliary neurotrophic factor enhances forebrain neurogenesis in adult mice.

Neurogenesis in the adult mammalian CNS occurs in the subventricular zone (SVZ) and dentate gyrus. The receptor for ciliary neurotrophic factor (CNTF), CNTFRalpha, is expressed in the adult subventricular zone. Because the in vitro effects of CNTF on neural precursors have been varied, including proliferation and differentiation into neurons or glia, we investigated its role in vivo. Injection of CNTF in the adult C57BL/6 mice forebrain increased the number of cells labeled with ip BrdU in both neurogenic regions. In the dentate gyrus, CNTF also appeared to enhance differentiation of precursors into neurons, i.e., increased the proportion of NeuN+/BrdU+ cells from approximately 14 to approximately 29%, but did not affect differentiation into astrocytes (GFAP+) or oligodendrocytes (CNPase+). In the SVZ, CNTF increased the proportion of GFAP+/BrdU+ cells from approximately 1 to approximately 2%. CNTF enhanced the distance of migration of new neurons into the granule cell layer. Intraventricular injection of neutralizing anti-CNTF antibodies reduced the number of BrdU-labeled cells in the SVZ. These results suggest that endogenous CNTF regulates adult neurogenesis by increasing proliferation of neural stem cells and/or precursors. Alternatively, CNTF could maintain cells longer in the S-phase, resulting in increased BrdU labeling. In the neurogenic region of the SVZ, CNTFRalpha was exclusively present in GFAP-positive process-bearing cells, suggesting that CNTF affects neurogenesis indirectly via neighboring astroglia. Alternatively, these cells may be part of the neural precursor lineage. The restricted expression of CNTF within the nervous system makes it a potential selective drug target for cell replacement strategies.

Animals↗