Endogenous Neurotrophic Factor Research Articles

Experimetal research Dexamethasone and vitamin B12 synergistically promote peripheral nerve regeneration in rats by upregulating the expression of brain-derived neurotrophic factor

IntroductionDexamethasone and vitamin B12 are currently used in the clinic to treat peripheral nerve damage but their mechanisms of action remain incompletely understood. In this study we hypothesized that dexamethasone and vitamin B12 promote the production of endogenous neurotrophic factors, thereby enhancing peripheral nerve repair.Material and methodsNinety-six adult male Wistar rats were employed to establish a sciatic nerve injury model. They were then randomly divided into 4 groups to be subjected to different treatment: saline (group A), dexamethasone (group B), vitamin B12 (group C), and dexamethasone combined with vitamin B12 (group D). The walking behavior of rats was evaluated by footprint analysis, and the nerve regeneration was assessed by electrophysiological analysis and ultrastructural examination. The expression of brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor, NT-3 and IL-6 in the injured sciatic nerves was detected by immunohistochemical and RT-PCR analysis.ResultsDexamethasone and vitamin B12 promoted the regeneration of myelinated nerve fibers and the proliferation of Schwann cells. Furthermore, dexamethasone and vitamin B12 promoted the recovery of sciatic functional index and sensory nerve conduction velocity, and upregulated BDNF expression in the injured sciatic nerves.ConclusionsDexamethasone and vitamin B12 promote peripheral nerve repair in a rat model of sciatic nerve injury through the upregulation of BDNF expression. These findings provide new insight into the neurotrophic effects of dexamethasone and vitamin B12 and support the application of these agents in clinical treatment of peripheral nerve injury.

A New Combined Therapeutic Strategy of Governor Vessel Electro-Acupuncture and Adult Stem Cell Transplantation Promotes the Recovery of Injured Spinal Cord

Spinal cord injury (SCI) is a very severe traumatic disease of the central nervous system (CNS). Because of its high incidence rate in causing disabilities, it brings great burdens to patients and society. Both Traditional Chinese Medicine (TCM) and Western Medicine have been adopted to ameliorate SCI with promising outcomes. In TCM, the use of Governor Vessel electro-acupuncture has achieved remarkable results on the rehabilitation of patients with SCI. In the past decade, Governor Vessel electro-acupuncture has also been used in experimentally induced SCI and this has resulted in promising functional recovery. Both neural stem cells (NSCs) and bone marrow mesenchymal cells (MSCs) have been used extensively in recent years for improvement of functional recovery of CNS disorders. We have used a combined approach by integrating the basic and clinical research in SCI in recent years. In this connection, transplantation of NSCs or MSCs coupled with the Governor Vessel electro-acupuncture (GV-EA) has been adopted to improve the recovery of SCI. Our study suggests that GV-EA may activate the process of cell metabolism, and initiate synthesis and secretion of endogenous neurotrophic factors in the ambient tissues at the lesion site of spinal cord. It is proposed that the new combined strategy could promote a better structural and functional recovery of injured spinal cord.

Treatment of rat spinal cord injury with the neurotrophic factor albumin-oleic acid: translational application for paralysis, spasticity and pain.

Sensorimotor dysfunction following incomplete spinal cord injury (iSCI) is often characterized by the debilitating symptoms of paralysis, spasticity and pain, which require treatment with novel pleiotropic pharmacological agents. Previous in vitro studies suggest that Albumin (Alb) and Oleic Acid (OA) may play a role together as an endogenous neurotrophic factor. Although Alb can promote basic recovery of motor function after iSCI, the therapeutic effect of OA or Alb-OA on a known translational measure of SCI associated with symptoms of spasticity and change in nociception has not been studied. Following T9 spinal contusion injury in Wistar rats, intrathecal treatment with: i) Saline, ii) Alb (0.4 nanomoles), iii) OA (80 nanomoles), iv) Alb-Elaidic acid (0.4/80 nanomoles), or v) Alb-OA (0.4/80 nanomoles) were evaluated on basic motor function, temporal summation of noxious reflex activity, and with a new test of descending modulation of spinal activity below the SCI up to one month after injury. Albumin, OA and Alb-OA treatment inhibited nociceptive Tibialis Anterior (TA) reflex activity. Moreover Alb-OA synergistically promoted early recovery of locomotor activity to 50±10% of control and promoted de novo phasic descending inhibition of TA noxious reflex activity to 47±5% following non-invasive electrical conditioning stimulation applied above the iSCI. Spinal L4–L5 immunohistochemistry demonstrated a unique increase in serotonin fibre innervation up to 4.2±1.1 and 2.3±0.3 fold within the dorsal and ventral horn respectively with Alb-OA treatment when compared to uninjured tissue, in addition to a reduction in NR1 NMDA receptor phosphorylation and microglia reactivity. Early recovery of voluntary motor function accompanied with tonic and de novo phasic descending inhibition of nociceptive TA flexor reflex activity following Alb-OA treatment, mediated via known endogenous spinal mechanisms of action, suggests a clinical application of this novel neurotrophic factor for the treatment of paralysis, spasticity and pain.

Gastric Inhibitory Polypeptide and its Receptor are Expressed in the Central Nervous System and Support Neuronal Survival

The development of neuronal apoptosis depends on an intrinsic transcriptional program. By DNA microarray technology, we have previously implicated a number of genes in different paradigms of neuronal apoptosis. In the present study, we investigated the spatiotemporal pattern of expression of two of these genes, gastric inhibitory polypeptide (Gip) and its receptor (Gipr) in the rat central nervous system. The levels of their transcripts were measured with real-time quantitative polymerase chain reaction and in situ-hybridization. Widespread expression of Gip and Gipr was found in adult rat brain, whereas during postnatal cerebellum development, they were highly expressed in the external and internal granule layer, and in Purkinje cells. To investigate the possible biological function of Gip we examined its effects in vitro. Addition of Gip to cultured cerebellar granule neurons reduced the extent of apoptotic death induced by switching the growing medium from 25 to 5 mM K+. This neurotrophic effect was mimicked by that of PACAP38 and IGF1. We conclude that Gip acts as an endogenous neurotrophic factor and supports neuronal survival.

P4‐422: Manipulation endogenous neurotrophic factors: A promising therapy in Alzheimer's disease (hypothetic study)

P4‐422: Manipulation endogenous neurotrophic factors: A promising therapy in Alzheimer's disease (hypothetic study)

P4‐423: RGS‐14(414) gene delivery into brain area V2 induces both the recovery and prevention of recognition memory in ageing and Alzheimer's disease

neurogenesis and maturation of newly generated neurons in the brain of subjects with AD and delay or prevent the progression of the disease is stimulation of endogenous neurotrophic factors. Neurotrophic factors a family of structurally related, secreted proteins, consisting of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), ciliary neurotrophic factor (CNTF), NT-3, and NT4/5, are small proteins that provide trophic events in neuronal cells. These secreted neurotrophic factors act by binding to the specific cell surface receptors that signal the neuron to survive. Methods: Neurotrophic factors are important in the developing and mature nervous system. They influence cell proliferation, survival, differentiation, migration, axon and dendritic growth and synaptic plasticity. They play critical roles in complex behaviors including anxiety, depression and learning. They can be given exogenously as pure proteins or through gene therapy to prevent nerve cell death caused by various insults including nerve injury, brain trauma, and exposure to toxins. Results: The high potency of neurotrophic factors, as shown by many experimental studies, makes them a rational candidate therapeutic agent in neurodegenerative disease. Because the administration of exogenous neurotrophic factors is time consuming and expensive for the most of patients and also it needs to gene delivery, intense care considerations and probably it’s side effects, therefore it seems that the manipulation of endogenous neurotrophic factors is suitable treatment for AD.Conclusions: It is concluded that the manipulation and stimulation of endogenous neurotrophic factors is a promising therapeutic strategy in Alzheimer’s disease.

Mimicking the Neurotrophic Factor Profile of Embryonic Spinal Cord Controls the Differentiation Potential of Spinal Progenitors into Neuronal Cells

Recent studies have indicated that the choice of lineage of neural progenitor cells is determined, at least in part, by environmental factors, such as neurotrophic factors. Despite extensive studies using exogenous neurotrophic factors, the effect of endogenous neurotrophic factors on the differentiation of progenitor cells remains obscure. Here we show that embryonic spinal cord derived-progenitor cells express both ciliary neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF) mRNA before differentiation. BDNF gene expression significantly decreases with their differentiation into the specific lineage, whereas CNTF gene expression significantly increases. The temporal pattern of neurotrophic factor gene expression in progenitor cells is similar to that of the spinal cord during postnatal development. Approximately 50% of spinal progenitor cells differentiated into astrocytes. To determine the effect of endogenous CNTF on their differentiation, we neutralized endogenous CNTF by administration of its polyclonal antibody. Neutralization of endogenous CNTF inhibited the differentiation of progenitor cells into astrocytes, but did not affect the numbers of neurons or oligodendrocytes. Furthermore, to mimic the profile of neurotrophic factors in the spinal cord during embryonic development, we applied BDNF or neurotrophin (NT)-3 exogenously in combination with the anti-CNTF antibody. The exogenous application of BDNF or NT-3 promoted the differentiation of these cells into neurons or oligodendrocytes, respectively. These findings suggest that endogenous CNTF and exogenous BDNF and NT-3 play roles in the differentiation of embryonic spinal cord derived progenitor cells into astrocytes, neurons and oligodendrocytes, respectively.

The chronic administration of cerebrolysin induces plastic changes in the prefrontal cortex and dentate gyrus in aged mice

Cerebrolysin (Cbl) is a mixture of neuropeptides with effects similar to the endogenous neurotrophic factors and is considered one of the best drugs used in the treatment of dementias such as Alzheimer's disease (AD). In brains with AD, morphological changes in the dendrites of pyramidal neurons of the prefrontal cortex (PFC) and hippocampus have been reported. These changes are reflected particularly in the decrement of both the dendritic tree and spine density. Here we evaluated the effect of this drug on the dendrites of pyramidal neurons of the PFC and CA1 dorsal hippocampus and granule cells from the dentate gyrus (DG) and medium spiny neurons of the nucleus accumbens (NAcc) of aged mice. Cbl (5 ml kg(-1) , i.p.) was administered daily for 60 days to 6-month-old mice. Dendritic morphology was studied by the Golgi-Cox stain procedure followed by Sholl analysis at 8 months ages. In all Cbl-treated mice a significant increase in dendritic spine density and dendritic length in pyramidal neurons of the PFC and granule cells of the DG was observed. Interestingly, the enhancement in dendritic length was close to the soma in pyramidal neurons of the PFC whereas in granule neurons of the DG the increase in dendritic length was further from the soma. Our results suggest that Cbl induces plastic modifications of dendritic morphology in the PFC and DG. These changes may explain the therapeutic effect seen in AD patients treated with Cbl.

Sensitivity of Dopaminergic Neuron Differentiation from Stem Cells to Chronic Low-Dose Methylmercury Exposure

Perinatal exposure to low doses of methylmercury (MeHg) can cause adult neurological symptoms. Rather than leading to a net cell loss, the toxicant is assumed to alter the differentiation and neuronal functions such as catecholaminergic transmission. We used neuronally differentiating murine embryonic stem cells (mESC) to explore such subtle toxicity. The mixed neuronal cultures that formed within 20 days contained a small subpopulation of tyrosine hydroxylase (TH)-positive neurons with specific dopaminergic functions such as dopamine transport (DAT) activity. The last 6 days of differentiation were associated with the functional maturation of already preformed neuronal precursors. Exposure to MeHg during this period downregulated several neuronal transcripts, without affecting housekeeping genes or causing measurable cell loss. Profiling of mRNAs relevant for neurotransmitter systems showed that dopamine receptors were coordinately downregulated, whereas known counterregulatory systems such as galanin receptor 2 were upregulated. The chronic (6 days) exposure to MeHg, but not shorter incubation periods, attenuated the expression levels of endogenous neurotrophic factors required for the maturation of TH cells. Accordingly, the size of this cell population was diminished, and DAT activity as its signature function was lost. When mixed lineage kinase activity was blocked during MeHg exposure, DAT activity was restored, and the reduction of TH levels was prevented. Thus, transcriptional profiling in differentiating mESC identified a subpopulation of neurons affected by MeHg, and a pharmacological intervention was identified that specifically protected these cells.

Cerebrolysin in Alzheimer's disease

Cerebrolysin is a neuropeptide preparation mimicking the action of endogenous neurotrophic factors. Positive effects of Cerebrolysin on β-amyloid- and tau-related pathologies, neuroinflammation, neurotrophic factors, oxidative stress, excitotoxicity, neurotransmission, brain metabolism, neuroplasticity, neuronal apoptosis and degeneration, neurogenesis and cognition were demonstrated in experimental conditions. These pleiotropic effects of Cerebrolysin on Alzheimer's disease-related pathogenic events are consistent with a neurotrophic-like mode of action, and seems to involve the activation of the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase-3 β intracellular signaling pathway. The clinical efficacy of Cerebrolysin in Alzheimer's disease was evaluated in several randomized, double-blind, clinical trials, showing consistent benefits on global clinical function and cognition, improvements in behavior at high doses, and minor effects on daily living activities in patients with mild to moderate Alzheimer's disease, as well as in subgroups of moderate to moderately severe patients. In addition, the clinical benefits of Cerebrolysin were largely maintained for several months after ending treatment, a finding that supports its discontinuous administration. Cerebrolysin was generally well tolerated and did not induce significant adverse events in Alzheimer's patients. Although long-term studies are needed, the data available suggest that Cerebrolysin is effective as monotherapy and constitutes a promising option for combined therapy in Alzheimer's disease.

The physiology of neural injury and regeneration: The role of neurotrophic factors

Injured nerves regenerate slowly and often over long distances. Prolonged periods for regenerating nerves to make functional connections with denervated targets prolong the period of isolation of the neurons from the target (chronic axotomy) and of the denervation of Schwann cells in the distal nerve pathways (chronic denervation). In an animal model, we demonstrated that prolonged axotomy and chronic denervation severely reduce the regenerative capacity of neurons to less to 10%. Concurrent reduction in neurotrophic factors, including brain- and glial-derived neurotrophic factors (BDNF and GDNF) in axotomized neurons and denervated Schwann cells, suggest that these factors are required to sustain nerve regeneration. Findings that exogenous BDNF and GDNF did not increase numbers of neurons that regenerate their axons in freshly cut and repaired rat nerves, but did increase the numbers significantly after chronic axotomy, are consistent with the view that there is sufficient endogenous neurotrophic factor supply in axotomized motoneurons and denervated Schwann cells to support nerve regeneration but that the reduced supply must be supplemented when target reinnervation is delayed. In addition, findings that BDNF is essential for the effectiveness of brief low frequency electrical stimulation in promoting nerve growth, provides further support for a central role of BNDF in motor nerve regeneration. Learning outcomes: Readers of this article will gain an understanding of the basis for poor functional outcomes of peripheral nerve injuries, even when surgical repair is possible.

Spotlight on Cerebrolysin in Dementia†

Cerebrolysin is a parenterally administered, porcine brain-derived peptide preparation that has pharmacodynamic properties similar to those of endogenous neurotrophic factors. In several randomized, double-blind trials of up to 28 weeks' duration in patients with Alzheimer's disease, Cerebrolysin was superior to placebo in improving global outcome measures and cognitive ability. A large, randomized comparison of Cerebrolysin, donepezil or combination therapy showed beneficial effects on global measures and cognition for all three treatment groups compared with baseline. Although not as extensively studied in patients with vascular dementia, Cerebrolysin has also shown beneficial effects on global measures and cognition in this patient population. Cerebrolysin was generally well tolerated in clinical trials, with dizziness (or vertigo) being the most frequently reported adverse event. Although further studies with Cerebrolysin, including longer term trials and further exploration of its use in combination with cholinesterase inhibitors, are needed to more clearly determine its place in the management of Alzheimer's disease and vascular dementia, available data suggest that Cerebrolysin is a useful addition to the treatment options available for dementia.

Cerebrolysin

Cerebrolysin is a parenterally administered, porcine brain-derived peptide preparation that has pharmacodynamic properties similar to those of endogenous neurotrophic factors. In several randomized, double-blind trials of up to 28 weeks' duration in patients with Alzheimer's disease, Cerebrolysin was superior to placebo in improving global outcome measures and cognitive ability. A large, randomized comparison of Cerebrolysin, donepezil or combination therapy showed beneficial effects on global measures and cognition for all three treatment groups compared with baseline. Although not as extensively studied in patients with vascular dementia, Cerebrolysin has also shown beneficial effects on global measures and cognition in this patient population. Cerebrolysin was generally well tolerated in clinical trials, with dizziness (or vertigo) being the most frequently reported adverse event. Although further studies with Cerebrolysin, including longer term trials and further exploration of its use in combination with cholinesterase inhibitors, are needed to more clearly determine its place in the management of Alzheimer's disease and vascular dementia, available data suggest that Cerebrolysin is a useful addition to the treatment options available for dementia.

The role of neurotrophic factors in nerve regeneration

This review considers the 2 sources of neurotrophic factors in the peripheral nervous system (PNS), the neurons and the nonneuronal cells in the denervated distal nerve stumps, and their role in axon regeneration. Morphological assessment of regenerative success in response to administration of exogenous growth factors after nerve injury and repair has indicated a role of the endogenous neurotrophic factors from Schwann cells in the distal nerve stump. However, the increased number of axons may reflect more neurons regenerating their axons and/or increased numbers of axon sprouts from the same number of neurons. Using fluorescent dyes to count neurons that regenerated their axons across a suture site and into distal nerve stumps, brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF) were found not to increase the number of neurons that regenerated their axons after immediate nerve repair. Nevertheless, the factors did reverse the deleterious effect of delayed nerve repair, indicating that the axons that regenerate into the distal nerve stump normally have access to sufficient levels of endogenous neurotrophic factors to sustain their regeneration, while neurons that do not have access to these factors require exogenous factors to sustain axon regeneration. Neurons upregulate neurotrophic factors after axotomy. The upregulation is normally slow, beginning after 7 days and occurring in association with a protracted period of axonal regeneration in which axons grow out from the proximal nerve stump across a suture site over a period of 1 month in rodents. This staggered axon regeneration across the suture site is accelerated by a 1-hour period of low-frequency electrical stimulation that simultaneously accelerates the expression of BDNF and its trkB receptor in the neurons. Elevation of the level of BDNF after 2 days to > 3 times that found in unstimulated neurons was accompanied by elevation of the level of cAMP and followed by accelerated upregulation of growth-associated genes, tubulin, actin, and GAP-43 and downregulation of neurofilament protein. Elevation of cAMP levels via rolipram inhibition of phosphodiesterase 4 mimicked the effect of the low-frequency electrical stimulation. In conclusion, the enhanced upregulation of neurotrophic factors in the electrically stimulated axotomized neurons accelerates axon outgrowth into the distal nerve stumps where endogenous sources of growth factors in the Schwann cells support the regeneration of the axons toward the denervated targets. The findings provide strong support for endogenous neurotrophic factors of axotomized neurons and of denervated Schwann cells playing a critical role in supporting axon regeneration in the PNS.

Neurotrophic factor expression in newborns with myelomeningocele: Preliminary data

Background Neurotrophic factors play a crucial role in the stimulation of sprouting, synaptic plasticity and reorganization after spinal cord damage. The aim of this study was to investigate the expression of some neurotrophic factors [brain derived neurotrophic factor (BDNF), glial derived neurotrophic factor (GDNF), and nerve growth factor (NGF)] in the cerebrospinal fluid (CSF) of newborns with myelomeningocele (MMC) and to determine their correlations with this malformation. Methods To measure the expression of BDNF, GDNF, and NGF, we collected CSF samples of six newborns during the neurosurgical operation to correct the open MMC and of 10 matched controls. Endogenous neurotrophic factor levels were quantified using a two-site immuno-enzymatic assay. The statistical analysis was performed using the Mann–Whitney two-tailed two-sample test. Findings In the CSF of patients analysis of neurotrophic factor expression showed a significant increase of BDNF, GDNF, and NGF compared to the mean level of the control group (445.8±82.3, 86.5±2.6, and 59.9±6.2 pg/mL, respectively, respect to 10.2±5.9, 19.9±11.3, and 15.3±2.6 pg/mL) ( p<0.001). Interpretation Our study shows an over-expression of neurotrophic factors in the CSF of newborns with MMC. This neurotrophin up-regulation may stimulate axonal sprouting and synaptic reorganization of the damaged neural cells at the site of spinal cord lesion. The neurotrophic factor up-regulation may represent a particularly important biochemical markers of spinal cord damage and might be associated with the severity of spine injury in MMC patients.

Absence of Ret Signaling in Mice Causes Progressive and Late Degeneration of the Nigrostriatal System

Support of ageing neurons by endogenous neurotrophic factors such as glial cell line–derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) may determine whether the neurons resist or succumb to neurodegeneration. GDNF has been tested in clinical trials for the treatment of Parkinson disease (PD), a common neurodegenerative disorder characterized by the loss of midbrain dopaminergic (DA) neurons. BDNF modulates nigrostriatal functions and rescues DA neurons in PD animal models. The physiological roles of GDNF and BDNF signaling in the adult nigrostriatal DA system are unknown. We generated mice with regionally selective ablations of the genes encoding the receptors for GDNF (Ret) and BDNF (TrkB). We find that Ret, but not TrkB, ablation causes progressive and adult-onset loss of DA neurons specifically in the substantia nigra pars compacta, degeneration of DA nerve terminals in striatum, and pronounced glial activation. These findings establish Ret as a critical regulator of long-term maintenance of the nigrostriatal DA system and suggest conditional Ret mutants as useful tools for gaining insights into the molecular mechanisms involved in the development of PD.

Upregulation of Neurotrophic Factors Selectively in Frontal Cortex in Response to Olfactory Discrimination Learning

We have previously shown that olfactory discrimination learning is accompanied by several forms of long-term enhancement in synaptic connections between layer II pyramidal neurons selectively in the piriform cortex. This study sought to examine whether the previously demonstrated olfactory-learning-task-induced modifications are preceded by suitable changes in the expression of mRNA for neurotrophic factors and in which brain areas this occurs. Rats were trained to discriminate positive cues in pair of odors for a water reward. The relationship between the learning task and local levels of mRNA for brain-derived neurotrophic factor, tyrosine kinase B, nerve growth factor, and neurotrophin-3 in the frontal cortex, hippocampal subregions, and other regions were assessed 24 hours post olfactory learning. The olfactory discrimination learning activated production of endogenous neurotrophic factors and induced their signal transduction in the frontal cortex, but not in other brain areas. These findings suggest that different brain areas may be preferentially involved in different learning/memory tasks.

Exogenous gangliosides, neuronal plasticity and repair, and the neurotrophins.

Gangliosides, a heterogeneous family of glycosphingolipids abundant in the brain, have been shown to affect neuronal plasticity during development, adulthood and aging. This review will examine old and recent evidence that exogenous gangliosides and in particular GM1, the prototype member of this family, exhibit multimodal neurotrophic effects. Since these compounds are a potential therapeutic tool for the treatment of various forms of acute or chronic neurodegenerative diseases, understanding the dynamic interplay of gangliosides and neuronal cells is essential in the effort to cure neurological disorders. Focus will be given to the novel and provocative hypothesis that gangliosides' neuroprotective properties may derive from their ability to mimic endogenous neurotrophic factors.

Sparing of behavior and basal extracellular dopamine after 6-hydroxydopamine lesions of the nigrostriatal pathway in rats exposed to a prelesion sensitizing regimen of amphetamine

Repeated administration of amphetamine leads to enduring augmentation of its behavioral-activating effects, enhanced dopamine (DA) release in striatal regions, and morphological changes in DA target neurons. Here we show that exposure to a 2-week escalating-dose regimen of amphetamine prevents behavioral asymmetries of forelimb use and spontaneous (drug-independent) turning behavior following unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal pathway made 7–14 days after termination of amphetamine treatment (Experiments 1–3). Exposure to three nonescalating injections of amphetamine 7 days before 6-OHDA lesions had no effect (Experiment 2). Prelesion amphetamine treatment led to normalization of basal extracellular levels of striatal DA as measured by microdialysis on days 11–14 and 25–28 after lesioning (Experiment 3). However, there were no significant differences between treatment groups in postmortem tissue levels of DA and its metabolites, indicating a dissociation between the DA depletion and the extracellular levels of DA as measured by microdialysis. Finally, rats exposed to the escalating amphetamine regimen had reduced lesion-induced loss of TH-IR cells in the ipsilateral DA cell body regions (Experiment 3). Thus, prelesion exposure to the escalating doses of amphetamine may render the cells resistant to the consequences of damage after subsequent 6-OHDA lesions, possibly by accelerating the development of compensatory changes in the DA neurons that typically accompany behavioral recovery. The potential role of amphetamine-induced endogenous neurotrophic factors in the behavioral sparing and normalization of basal extracellular DA levels observed after subsequent 6-OHDA lesions is discussed.

Cabergoline Stimulates Synthesis and Secretion of Nerve Growth Factor, Brain-Derived Neurotrophic Factor and Glial Cell Line-Derived Neurotrophic Factor by Mouse Astrocytes in Primary Culture

Neuroprotection is the primary concern in patients with newly diagnosed Parkinson’s disease. The D₂/weak D₁ dopamine agonist cabergoline elicits neuroprotection by antioxidation and scavenging free radicals, and may protect neurons by up-regulating endogenous neurotrophic factors synthesis in the brain. In primary cultured mouse astrocytes, cabergoline 37 µmol/l immediately elevated concentrations of nerve growth factor, brain-derived neurotrophic factor, and glial cell line-derived neurotrophic factor (GDNF) in culture medium, reaching 9.9-, 2.6- and 30-fold, respectively, of control levels at 16 h. Relative mRNA levels were 3.0-, 1.5- and 1.9-fold, respectively, of controls at 3 h. These effects may be mediated partly by the dopamine D₂ receptor. Cabergoline may be a good candidate for an inducer of GDNF, which may have neuroprotective and neurorestorative properties in dopaminergic nigral neurons.