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Photon or near-infrared light therapy (NILT) may be an effective neuroprotective method to reduce behavioral dysfunction following an acute ischemic stroke. We evaluated the effects of continuous wave (CW) or pulse wave (P) NILT administered transcranially either 6 or 12 h following embolization, on behavioral outcome. For the studies, we used the rabbit small clot embolic stroke model (RSCEM) using three different treatment regimens: 1) CW power density of 7.5 mW/cm(2); 2) P1 using a frequency of 300 mus pulse at 1 kHz or 3) P2 using a frequency of 2 ms pulse at 100 Hz. Behavioral analysis was conducted 48 h after embolization, allowing for the determination of the effective stroke dose (P(50)) or clot amount (mg) that produces neurological deficits in 50% of the rabbits. Using the RSCEM, a treatment is considered beneficial if it significantly increases the P(50) compared with the control group. Quantal dose-response analysis showed that the control group P(50) value was 1.01+/-0.25 mg (n=31). NILT initiated 6 h following embolization resulted in the following P(50) values: (CW) 2.06+/-0.59 mg (n=29, P=0.099); (P1) 1.89+/-0.29 mg (n=25, P=0.0248) and (P2) 1.92+/-0.15 mg (n=33, P=0.0024). NILT started 12 h following embolization resulted in the following P(50) values: (CW) 2.89+/-1.76 mg (n=29, P=0.279); (P1) 2.40+/-0.99 mg (n=24, P=0.134). At the 6-h post-embolization treatment time, there was a statistically significant increase in P(50) values compared with control for both pulse P1 and P2 modes, but not the CW mode. At the 12-h post-embolization treatment time, neither the CW nor the P1 regimens resulted in statistically significant effect, although there was a trend for an improvement. The results show that P mode NILT can result in significant clinical improvement when administered 6 h following embolic strokes in rabbits and should be considered for clinical development.

Prosaposin is a 517 amino acid membrane component and secreted protein 5. , 7. , 9. that is proteolytically cleaved to generate the four small glycoproteins; saposins A, B, C and D. 9. , 13. , 19. Prosaposin’s ability to promote neurite outgrowth 31 and to protect neurons from programmed cell death 28 in vitro , as well as to rescue neurons from ischemia and other damage in vivo 11. , 12. , 15. , 25. implied that prosaposin was neurotrophic/neuroprotectant. 1. , 7. , 24. , 31. The neurotrophic sequence of prosaposin was isolated to smaller peptide fragments termed prosaptides 15. , 31. within the amino terminal portion of saposin C. 1. , 6. , 8. , 10. , 17. , 20. , 21. , 28. The proposed use of synthetic prosaptides as peripherally administered neuroprotective and/or neurotrophic therapeutic agents has stemmed from their ability to cross the blood–brain barrier, 27 as well as their reported neurotrophic activity in vitro . 15. , 23. , 31. Few studies, however, have attempted to characterize these peptides, presumably due to their reported instability following peripheral administration. 27 With the recent design of a stable 11-mer retro-inverso prosaptide, 15. , 31. it has become feasible to investigate the pharmacological effects of a stable version of these peptides in the validated rabbit spinal cord ischemia model that has been used extensively in the development of therapeutics to treat ischemic stroke. 4. , 14. , 16. , 18. Our results show not only that prosaptide was not neurotrophic/neuroprotectant in vivo , but rather it worsened ischemia-induced behavioral deficits.

Glial cell line-derived neurotrophic factor was initially identified as a survival factor for developing midbrain dopamine neurons (for reviews, see Refs 17 and 19). Subsequent studies have demonstrated a more wide-spread role for glial cell line-derived neurotrophic factor in the developing and adult CNS. In the adult rat brain, for instance, prior administration of glial cell line-derived neurotrophic factor protects nigrostriatal dopamine neurons from 6-hydroxydopamine-induced damage. When given several weeks after 6-hydroxydopamine injection, glial cell line-derived neurotrophic factor also restores the function of these neurons. Glial cell line-derived neurotrophic factor attenuates excitotoxin-induced cell death in the striatum and hippocampal formation and protective effects of glial cell line-derived neurotrophic factor following axotomy have been reported for spinal motor neurons and basal forebrain cholinergic neurons. These findings suggest that glial cell line-derived neurotrophic factor may be a protective/restorative agent for a diverse population of neurons and imply that it may be a useful therapeutic tool for a variety of neurodegenerative diseases including Parkinson's, Huntington's and Alzheimer's diseases. The potential receptor mediating the pleiotropic effects of glial cell line-derived neurotrophic factor has been characterized only recently as a novel glycosyl-phosphatidylinositol-linked protein, GDNFR-alpha. Because GDNFR-alpha is a cell surface receptor, an additional protein(s) was thought to be involved in the glial cell line-derived neurotrophic factor signalling cascade. The identity of the likely candidate, ret, was inferred initially from indirect evidence. Not only were there remarkable similarities in the distribution of glial cell line-derived neurotrophic factor and the proto-oncogene ret in the developing rat and mouse brain, but also in the phenotype of glial cell line-derived neurotrophic factor knockout mice and mice with ret mutations. Mice with either mutation exhibited pronounced renal and enteric abnormalities, implicating the receptor tyrosine kinase protein product of the ret proto-oncogene as the glial cell line-derived neurotrophic factor signalling protein. More conclusive evidence showing that activation of GDNFR-alpha by glial cell line-derived neurotrophic factor induces phosphorylation of ret has confirmed ret as a signalling protein for glial cell line-derived neurotrophic factor. Preliminary results showing that 6-hydroxydopamine lesions of the substantia nigra markedly reduced ret messenger RNA expression, established its localization to presumably glial cell line-derived neurotrophic factor-responsive dopamine neurons in the nigrostriatal pathway. In contrast, it is not clear whether other glial cell line-derived neurotrophic factor-responsive neurons in the CNS, such as the basal forebrain cholinergic neurons and striatal neurons, also express ret, nor is it evident whether levels of the protein are regulated by disruption of the respective pathways. The present study shows that dense networks of ret immunoreactivity are distributed throughout the nigrostriatal pathway, with lower densities of staining in other brain regions, including the septohippocampal pathway. Following extensive unilateral 6-hydroxydopamine lesions of the medial forebrain bundle, ret immunoreactivity in the substantia nigra and striatum was reduced significantly, to a similar extent as tyrosine hydroxylase immunoreactivity. In contrast, excitotoxic lesions of the striatum, achieved by intrastriatal quinolinic acid injections, resulted in increased ret staining in this brain region. In addition, marked decrements in septal ret immunoreactivity were consequent to complete transections of the fimbria-fornix.

The present study determined whether molecules normally associated with immune signalling processes, specifically the lymphokines interleukin-1 beta, -2, -3 and -6, can be detected in the human hippocampal formation, and whether their levels are altered in neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Interleukin-1 beta, -2, -3 and -6 were measured in post mortem tissues from 14 control neurologically normal subjects, 24 patients with Alzheimer's disease and 17 patients with Parkinson's disease. In order to assess the extent of the cholinergic deficit in the Alzheimer's disease brains, choline acetyltransferase activity in the hippocampal formation was first determined. In the Alzheimer's disease tissues, choline acetyltransferase activity was significantly reduced (by 58%) compared to the control hippocampi, whereas that in the Parkinson's disease hippocampi was not significantly different from control. Using radioimmunoassays with antisera specific for the respective interleukin, marked increases in the content of immunoreactive interleukin-1 beta (99%), interleukin-2 (129%) and interleukin-3 (64%) could be detected in the Alzheimer's, but not the Parkinson's disease hippocampi. Interleukin-6 levels were not significantly different in either group, compared to the control hippocampi. Since striking elevations in various interleukins were detected in the Alzheimer's disease hippocampi, the possibility that concomitant alterations in interleukin receptor sites also occurred was investigated. Using radioligand binding to hippocampal membranes, low levels of interleukin binding were measured in the control hippocampi. In the Alzheimer's tissues, significant elevations in [125I]interleukin-1 beta (by 65%) and [125I]interleukin-2 (by 69%) binding were noted. In contrast, [125I]interleukin-3 binding was not different in the Alzheimer's disease compared to the control tissues. In the hippocampal formation of Parkinson's disease brains, only [125I]interleukin-2 binding was significantly increased (by 80%). In summary, the present results indicate that there is pronounced activation of immune system function, particularly specific immune mediators such as the interleukins, in the hippocampal formation in Alzheimer's disease, and further suggest that stimulation of immune function may be an integral component of the pathological changes that occur in this disease.

Recent studies with nerve growth factor (NGF) have identified the pharmacological actions of this neurotrophin in a variety of animal models that mimic some of the neurotransmitter deficits that occur in Alzheimer's disease (AD, for reviews see Refs 7, 15, 17, 19). Based upon extensive pharmacological studies, NGF has been characterized as a crucial maintenance factor for adult cholinergic neurons of the septo-hippocampal and basalo-cortical pathways. Among the reported actions of NGF is an attenuation of lesion-induced decrements in presynaptic and postsynaptic cholinergic markers and functions in the hippocampal formation. Thus, in studies that used partial fimbriectomies to parallel the cholinergic neurodegeneration that occurs in AD, intraventricularly administered nerve growth factor prevented the loss of choline acetyltransferase (ChAT) and acetylcholinesterase immunoreactivity in the septum and increased a variety of presynaptic cholinergic markers involved in the synthesis, storage and release of the neurotransmitter acetylcholine (for reviews see Refs 7, 17, 19). More specifically, chronic NGF treatment attenuates lesion-induced reductions in hippocampal ChAT activity and high-affinity choline uptake, the end-result of which is an enhanced capacity to synthesize acetylcholine. This increased acetylcholine synthesis, in turn, appears to translate directly into augmented vesicular storage and release of the neurotransmitter. For instance, not only does NGF treatment reverse lesion-induced reductions in maximal binding densities of the acetylcholine vesicular transport marker [3H]vesamicol, but it also enhances acetylcholine release and turnover rate. NGF treatment also appears to restore the sensitivity of postsynaptic muscarinic receptors to agonist-induced stimulation following partial fimbriectomies.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of chronic intraventricular administration of recombinant human nerve growth factor on hippocampal muscarinic receptor densities and muscarinic receptor-linked second messenger systems were determined in adult rats 21 days following partial or full unilateral fimbrial transections. First, autoradiographic analysis of muscarinic receptors was carried out using [3H]quinuclidinyl benzilate for total muscarinic receptors, [3H]pirenzepine for M1 receptors and [3H]AF-DX 384 for M2 receptors. Partial fimbrial transections did not significantly alter the density of these muscarinic receptor populations in the dorsal or ventral hippocampus and there was no effect of chronic (1 micrograms every other day, 21 days) recombinant human nerve growth factor treatment. In contrast, in animals receiving full fimbrial transections which by themselves did not alter muscarinic receptor density, recombinant human nerve growth factor treatment increased the density of [3H]quinuclidinyl benzilate binding sites, M1 receptors, and M2 receptors by approximately 40% in the CA1 region. Secondly, we determined the effect of chronic recombinant human nerve growth factor treatment on muscarinic receptor-mediated second messenger production in rats with either partial or full unilateral fimbrial transections. In partially fimbriectomized rats, oxotremorine-induced inositol triphosphate production by hippocampal slices was increased by 81% on the lesioned side of animals treated with a control protein. This lesion-induced supersensitivity of M1 muscarinic receptor function was prevented by chronic recombinant human nerve growth factor treatment. In recombinant human nerve growth factor-treated animals, inositol triphosphate production was similar to values on unlesioned control sides. The muscarinic receptor-mediated increase in cyclic GMP levels was not altered by fimbrial transections or recombinant human nerve growth factor treatment. In animals with full unilateral fimbrial transections, oxotremorine-induced inositol triphosphate production was increased by 99% on the lesioned side of animals treated with a control protein and treatment with recombinant human nerve growth factor did not alter this denervation-induced supersensitivity of muscarinic receptor transduction signal. Chronic recombinant human nerve growth factor treatment did not affect the levels of inositol triphosphate on the contralateral unlesioned side of either partial or full fimbriectomized animals. Earlier studies indicate that chronic nerve growth factor treatment increases the presynaptic function of hippocampal cholinergic neurons surviving partial fimbrial transections. The findings of the present study indicate that these presynaptic effects translate into functional changes at the level of postsynaptic muscarinic receptors in the hippocampus.(ABSTRACT TRUNCATED AT 400 WORDS)

Brain-derived neurotrophic factor is selectively expressed at relatively high levels in the rat hippocampal formation (for review, see Ref. 12; see also Refs 8, 13, 19, 20, 27) where it is thought to be involved in mechanisms of neurodegeneration and/or neural protection related to the plasticity of hippocampal neurons. Functional responses to brain-derived neurotrophic factor appear to be mediated by a tyrosine receptor kinase B with the possible involvement of the p75 low-affinity nerve growth factor receptor protein. Among the many characteristics of Alzheimer's disease is an upregulation of immune mediators in and around senile plaques in Alzheimer's disease. Recently, interleukin-1 has been shown to be detrimental to the long-term survival of embryonic hippocampal neurons in culture. Thus, if the same occurs in vivo, it is possible that the accumulation of interleukin-1 in Alzheimer's disease hippocampus may be responsible for altered hippocampal neuron synaptic plasticity. This may occur either by a direct action of interleukin-1 on hippocampal neurons or possibly indirectly by stimulating beta-amyloid production. Other indirect mechanisms may involve growth or survival factors such as the neurotrophin brain-derived neurotrophic factor which is thought to play an important role in the plastic responses of hippocampal neurons. A recent study showed that brain-derived neurotrophic factor mRNA is selectively decreased in the dentate gyrus in Alzheimer's disease. The reason(s) for the decrease of brain-derived neurotrophic factor mRNA is not known, but one possibility may be associated with the enhanced expression of interleukin-1 in the hippocampus of Alzheimer's disease patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Quantitative in situ hybridization and northern blot analysis techniques were used to determine the effects of removal of the cholinergic input on levels and topographical distribution of brain-derived neurotrophic factor mRNA in the hippocampus of adult rats. First, the effects of partial and full fimbrial transections, which result in partial and near-total cholinergic deafferentation respectively, were compared. Twenty-one days after partial unilateral fimbrial transections, there were significant decreases in brain-derived neurotrophic factor mRNA expression throughout the hippocampal formation. Decreased expression of brain-derived neurotrophic factor mRNA was evident in all areas of localization within the hippocampal formation. The decreases amounted to 22–36% reductions compared with unlesioned control animals. Brain-derived neurotrophic factor mRNA levels were decreased to a greater extent (50–69%) following full unilateral fimbrial transections. Quantitative northern blot analysis indicated that hippocampal BDNF mRNA was decreased by 29 and 68%, three weeks after partial or full unilateral fimbrial transections, respectively. The extent of the reductions in brain-derived neurotrophic factor mRNA levels correlated with reductions in acetylcholinesterase staining density and cholinergic terminal density determined by quantitative autoradiographic analysis of [ 3 H]vesamicol binding sites. Second, we found that chronic treatment with atropine (20 mg/kg per day for 14 days) decreased (by 54%) brain-derived neurotrophic factor mRNA levels in all areas of localization within the hippocampus. In contrast, chronic treatment with nicotine (1.18 mg/kg per day for 14 days), a treatment known to desensitize nicotinic receptors, did not affect brain-derived neurotrophic factor mRNA expression in the hippocampal formation. The findings provide evidence for cholinergic muscarinic regulation of brain-derived neurotrophic factor mRNA expression in the adult rat hippocampal formation and they suggest the existence of a tonic stimulation of brain-derived neurotrophic factor synthesis by the cholinergic afferents.

The effects of intranigrally- or intraventricularly-administered glial cell line-derived neurotrophic factor were tested on low dose (0.05 mg/kg) apomorphine-induced rotations and tyrosine hydroxylase activity in the substantia nigra and striatum of stable 6-hydroxydopamine-lesioned rats. In addition, we determined if 6-hydroxydopamine lesions in the absence or presence of treatment affected neuropeptide (substance P, met-enkephalin, dynorphin) content in the striatum. Glial cell line-derived neurotrophic factor, when administered intranigrally, prevented apomorphine-induced rotational behaviour for 11 weeks following a single injection. In comparison, intraventricularly-administered glial cell line-derived neurotrophic factor produced a transient reduction in rotational behaviour that lasted for two to three weeks following a single injection. We also show that rotational behaviour is reduced following each subsequent intraventricular injection of glial cell line-derived neurotrophic factor given every six weeks, a time-point when baseline rotation deficits were re-established. Intranigrally- or intraventricularly-administered glial cell line-derived neurotrophic factor significantly reduced weight gain in all 6-hydroxydopamine-lesioned rats in this study. Following behavioural analysis where a confirmed improvement of behaviour was established, tissues were dissected for neurochemical analysis. In lesioned rats with intranigral injections of administered glial cell line-derived neurotrophic factor, significant increases of nigral, but not striatal tyrosine hydroxylase activity were measured. Additionally, 6-hydroxydopamine lesions significantly increased striatal dynorphin (61-139%) and met-enkephalin (81-139%), but not substance P levels. In these rats, intranigrally-administered glial cell line-derived neurotrophic factor injections reversed lesion-induced increases in nigral dynorphin A levels and increased nigral dopamine levels, but did not alter nigral met-enkephalin or substance P levels nor striatal dopamine levels. In lesioned rats with intraventricular injections of glial cell line-derived neurotrophic factor, tyrosine hydroxylase ispilateral to the lesion was increased in the substantia nigra, but not in the striatum. Intraventricularly-administered glial cell line-derived neurotrophic factor did not reverse lesion-induced increases in nigral dynorphin A or met-enkephalin levels nor did glial cell line-derived neurotrophic factor affect substance P levels in the striatum. These results suggest that in an animal model of Parkinson's disease, the neurotrophic factor glial cell line-derived neurotrophic factor reverses behavioural consequences of 6-hydroxydopamine administration, an effect that may involve both dopaminergic and peptidergic neurotransmission.

The present study determined the effects of chronic intranigral injections of recombinant human brain-derived neurotrophic factor (1 μg) every second day for 19 days on the functional capacity of dopaminergic neurons of the nigrostriatal pathway of unlesioned adult rats. In animals chronically treated with brain-derived neurotrophic factor, we observed amphetamine (5 mg/kg)-induced circling behavior directed toward the neurotrophin-injected side (33 turns/5 min). The behavioral asymmetry was paralleled by reductions of striatal [ 3 H]dopamine uptake (27%), tyrosine hydroxylase activity (68%), dopamine content (36%) and [ 3 H]mazindol binding site density (35%) on the same side as brain-derived neurotrophic factor treatment. While chronic injections of brain-derived neurotrophic factor produced a modest decrease in the number of tyrosine hydroxylase-positive cell bodies in the vicinity of the injection site, a similar reduction in cell number was observed in animals injected with a control protein, cytochrome c. However, in contrast to the animals treated with brain-derived neurotrophic factor, rats treated with the control protein showed no amphetamine-induced circling behavior, and there were no significant reductions in neurochemical parameters of striatal dopaminergic function. Lastly, we found that in brain-derived neurotrophic factor-injected animals there was a 30% decrease of tyrosine hydroxylase messenger RNA levels in the ventral mesencephalon. We also determined the effects of brain-derived neurotrophic factor treatment on animals with transections of the medial forebrain bundle. Medial forebrain bundle-lesioned animals challenged with amphetamine circled (55 turns/5 min) ipsilateral to the lesioned side. The medial forebrain lesions decreased the following markers of striatal dopaminergic function: [ 3 H]dopamine uptake (65%), tyrosine hydroxylase activity (79%), dopamine content (80%) and [ 3 H]mazindol binding site density (52%), induced a pronounced loss of tyrosine hydroxylase-positive cell bodies within the substantia nigra and also reduced tyrosine hydroxylase messenger RNA levels. Chronic intranigral brain-derived neurotrophic factor treatment did not attenuate nor did it exacerbate the medial forebrain bundle lesion-induced decreases of dopaminergic parameters in either the substantia nigra or striatum. The results of the present study indicate that chronic intranigral administration of brain-derived neurotrophic factor to normal adult rats induces a dopaminergic hypofunction in the striatum which is manifested behaviorally by amphetamine-induced rotations. The brain-derived neurotrophic factorinduced striatal function is not the result of significant cell loss at the levels of the substantia nigra, but seems to be related to brain-derived neurotrophic factor-induced down-regulation of dopaminergic-specific proteins. In addition, we found that chronic brain-derived neurotrophic factor treatment does not attenuate the loss of striatal dopaminergic function following transection of the medial forebrain bundle.

The present study determined the effects of chronic recombinant human nerve growth factor administration [1 microgram given intracerebroventricularly q.i.d. (every other day) for three weeks] on in vivo hippocampal cholinergic function in adult rats with unilateral partial fimbrial transections. Partial fimbrial transections did not significantly alter the levels of endogenous acetylcholine or [2H4]acetylcholine in the hippocampus due to functional compensation by surviving cholinergic terminals. In animals chronically treated with nerve growth factor, the levels of endogenous choline, endogenous acetylcholine, [2H4]choline and [2H4]acetylcholine accumulated in the hippocampus on the lesioned side were not significantly different from those on the contralateral unlesioned side or from values measured in animals treated with cytochrome c, a control protein. However, changes in cholinergic parameters induced by the partial lesions or recombinant human nerve growth factor treatment became manifest when animals were challenged using pharmacological agents such as pentylenetetrazole or pilocarpine given after lithium chloride pretreatment. First, in nerve growth factor-treated animals administered the general stimulant pentylenetetrazole (10 mg/kg) 2 min prior to measuring in vivo cholinergic parameters, we observed a significant increase in the hippocampal content of [2H4]choline in both lesioned and unlesioned hippocampi. The magnitude of the increase was significantly higher on the lesioned compared to the unlesioned side. Although chronic recombinant human nerve growth factor treatment induced increases of hippocampal [2H4]choline levels, there were no concomitant increases in the level of [2H4]acetylcholine. Second, in nerve growth factor-treated animals administered lithium chloride (3 mmol/kg) 20 h prior to pilocarpine (30 mg/kg), we observed a significant enhancement of the content of endogenous acetylcholine in the hippocampus of the lesioned side. Partial fimbrial transections also reduced in vitro cholinergic parameters reflecting endogenous acetylcholine levels in hippocampal slices. The content of endogenous acetylcholine in the slices was decreased by approximately 50% and chronic nerve growth factor treatment significantly elevated this value to approximately non-lesioned control values. Similarly, reductions in spontaneous and veratridine-evoked release of endogenous acetylcholine induced by partial fimbrial transections were counteracted by recombinant human nerve growth factor treatment. These findings demonstrate that chronic recombinant human nerve growth factor treatment effectively enhances the in vivo and in vitro synthesis, storage and release of endogenous acetylcholine. The results from the in vivo studies suggest that recombinant human nerve growth factor-induced differences in functional performance of hippocampal neurons may only be manifest during behavioral and/or pharmacological stimulation.

In situ hybridization techniques were used to analyse the spatiotemporal pattern of brainderived neurotrophic factor messenger RNA elevation associated with kainic acid-induced seizure activity in the rat. Pronounced increases in hippocampal brain-derived neurotrophic factor messenger RNA levels were observed as early as 30 min following the onset of behavioral seizures. The greatest increase (10-fold) occurred in the dentate granule cell layer, while pyramidal layers CA1, CA3, and CA4 exhibited increases of two- to six-fold. Peak elevation of brain-derived neurotrophic factor messenger RNA in CA1 hippocampal region was evident at 4 h in CA3, and in the dentate granule layer at 30 min postseizure. Elevations persisted in the dentate and hilar regions to four days, while the increases in CA1 and CA3 returned to control levels by 16 h following seizure. Significant increases in brain-derived neurotrophic factor messenger RNA were also observed in the superficial layers of cortex (II and III) and in the piriform cortex which reached peak elevations by 8 h. No detectable changes were observed in the dorsomedial thalamus. Although histologically defined pyramidal and granule cell layers displayed relatively uniform increases in brain-derived neurotrophic factor messenger RNA in response to kainate, a closer examination of the labeling patterns using emulsion autoradiography revealed discrete areas of high grain densities overlapping uniform, moderate hybridization densities in the dentate granule cell layer and CA3, suggesting that the capacity to upregulate brain-derived neurotrophic factor messenger RNA in these regions may differ among individual neurons. In conclusion, our studies revealed that brain-derived neurotrophic factor messenger RNA induction in response to systemic kainate administration differs in hippocampal and cortical areas, in magnitude, time of onset and duration. The observed temperospatial pattern does not correspond in a simple way to increases in metabolic or electrical activity associated with seizures or neuronal vulnerability coincident with the seizures.

To determine whether intraventricular administration of nerve growth factor alters presynaptic cholinergic function in the intact hippocampus or following partial lesions of the fimbria, we investigated the effects of recombinant human nerve growth factor treatment on [3H]acetylcholine synthesis and release by hippocampal slices following various treatment regimens. For chronic nerve growth factor treatment, 1 microgram of recombinant human nerve growth factor was injected intraventricularly every second day. Lesions reduced [3H]acetylcholine synthesis (by 48%) and spontaneous and evoked [3H]acetylcholine release by 35 and 61%, respectively. Chronic nerve growth factor treatment over three weeks elevated [3H]acetylcholine synthesis (by 39%) and spontaneous and evoked [3H]acetylcholine release by 27 and 64%, respectively, over values in lesioned hippocampi of animals treated with a control protein (cytochrome c). The nerve growth factor-induced enhancement of presynaptic cholinergic function persisted for three weeks following the termination of nerve growth factor administration. Furthermore, chronic (nine-week) treatment with nerve growth factor increased [3H]acetylcholine by 118% over values in lesioned hippocampi of animals treated with cytochrome c. These findings indicate that chronic treatment with recombinant human nerve growth factor increases the capacity of hippocampal cholinergic neurons surviving a partial fimbrial transection to synthesize, store and release acetylcholine. Application of recombinant human nerve growth factor during the initial weeks after lesioning was necessary to product significant elevations in acetylcholine synthesis, since chronic recombinant human nerve growth factor treatment after delays of three or more weeks were ineffective. Furthermore, chronic nerve growth factor treatment failed to stimulate acetylcholine synthesis and release in intact hippocampal cholinergic systems. Single intraventricular injections of recombinant human nerve growth factor at the time of lesioning resulted in a small decrease in acetylcholine synthesis which, however, was not accompanied by a change in the rate of evoked acetylcholine release from cholinergic neurons surviving the lesion. The study indicates that chronic or repeated administration of nerve growth factor during the onset of degenerative events is necessary for the stimulation of presynaptic cholinergic function in the hippocampus of adult rats with partial fimbrial transections.