Article A Non-invasive System for Delivering Neural Growth Factors across the Blood-Brain Barrier: A Review was published on January 1, 1998 in the journal Reviews in the Neurosciences (volume 9, issue 1).
Intraventricular administration of nerve growth factor (NGF) in rats has been shown to reduce age-related atrophy of central cholinergic neurons and the accompanying memory impairment. Intraventricular administration of NGF is necessary because NGF will not cross the blood-brain barrier (BBB). Here we have used a novel carrier system, consisting of NGF covalently linked to an anti-transferrin receptor antibody (OX-26), to transport biologically active NGF across the BBB. In our experiment, aged (24 months old) Fischer 344 rats received intravenous injections of the OX-26-NGF conjugate or a control solution (a mixture of unconjugated OX-26 and NGF) twice weekly for 6 weeks. The OX-26-NGF injections resulted in a significant improvement in spatial learning in previously impaired rats but disrupted the learning ability of previously unimpaired rats. Neuroanatomical analyses showed that OX-26-NGF conjugate treatment resulted in a significant increase in cholinergic cell size in the medial septal region of rats initially impaired in spatial learning. These results indicate the potential use of the transferrin receptor antibody delivery system for treatment of CNS disorders with neurotrophic proteins.
Dopamine (DA) neurotransmission has been implicated in several neurological and psychiatric disorders. The dopamine transporter (DAT) is highly expressed in dopaminergic neurons of the ventral mesencephalon and regulates neurotransmission by transporting DA back into the presynaptic terminals. To mediate restricted DNA recombination events into DA neurons using the Cre/loxP technology, we have generated a knockin mouse expressing Cre recombinase under the transcriptional control of the endogenous DAT promoter. To minimize interference with DAT function by preservation of both DAT alleles, Cre recombinase expression was driven from the 3' untranslated region (3'UTR) of the endogenous DAT gene by means of an internal ribosomal entry sequence. Crossing this murine line with a LacZ reporter showed colocalization of DAT immunocytochemistry and beta-galactosidase staining in all regions analyzed. This knockin mouse can be used for generating tissue specific knockouts in mice carrying genes flanked by loxP sites, and will facilitate the analysis of gene function in dopaminergic neurons.
Formation of lasting memories is believed to rely on structural alterations at the synaptic level. We had found that increased neuronal activity down-regulates Nogo receptor-1 (NgR1) in brain regions linked to memory formation and storage, and postulated this to be required for formation of lasting memories. We now show that mice with inducible overexpression of NgR1 in forebrain neurons have normal long-term potentiation and normal 24-h memory, but severely impaired month-long memory in both passive avoidance and swim maze tests. Blocking transgene expression normalizes these memory impairments. Nogo, Lingo-1, Troy, endogenous NgR1, and BDNF mRNA expression levels were not altered by transgene expression, suggesting that the impaired ability to form lasting memories is directly coupled to inability to down-regulate NgR1. Regulation of NgR1 may therefore serve as a key regulator of memory consolidation. Understanding the molecular underpinnings of synaptic rearrangements that carry lasting memories may facilitate development of treatments for memory dysfunction.
Nerve growth factor (NGF) is essential for the survival of both peripheral ganglion cells and central cholinergic neurons of the basal forebrain. The accelerated loss of central cholinergic neurons during Alzheimer's disease may be a determinant of dementia in these patients and may therefore suggest a therapeutic role for NGF. However, NGF does not significantly penetrate the blood-brain barrier, which makes its clinical utility dependent on invasive neurosurgical procedures. When conjugated to an antibody to the transferrin receptor, however, NGF crossed the blood-brain barrier after peripheral injection. This conjugated NGF increased the survival of both cholinergic and noncholinergic neurons of the medial septal nucleus that had been transplanted into the anterior chamber of the rat eye. This approach may prove useful for the treatment of Alzheimer's disease and other neurological disorders that are amenable to treatment by proteins that do not readily cross the blood-brain barrier.
Abstract The purpose of this project was to investigate ethanol influence on the development of serotonin‐containing (5‐HT) neurons of the dorsal raphe nucleus in rat. Fetal tissue of embryonic day 17 from the dorsal brainstem was grafted to the anterior chamber of the eye of adult albino rats. The experimental group was exposed to 16% ethanol in the drinking water, and the control group received water ad libitum. After 4 weeks, morphological and electrophysiological evaluations were performed. Immunohistochemical analysis showed that 5‐HT‐immunoreactive fibers from ethanol treated transplants had a disturbed outgrowth pattern into the host iris as compared to the control group. Furthermore, the outgrowth area and axon bundle formation was significantly greater in the control group than in the ethanol group. Electrophysiological recordings revealed a dose‐dependent biphasic effect of locally applied ethanol on transplanted monoaminergic neurons. Low doses of ethanol (0.5–3 mM)induced an increase in basal firing rate of control neurons, while higher doses (10–100 mM)caused inhibition. However, monoaminergic neurons in the ethanol group showed a decreased neuronal sensitivity to locally applied ethanol. The same dose of locally applied ethanol which produced an excitation of neuronal activity in the ethanol transplants produced an inhibition in the control grafts. The dose‐response curve was shifted to the right. The present results suggest that chronic ethanol exposure during early development leads to altered axonal outgrowth from brainstem 5‐HT neurons, as well as decreased sensitivity of these neurons to locally applied ethanol.
