Bridging grafts and transient nerve growth factor infusions promote long-term central nervous system neuronal rescue and partial functional recovery.

Abstract

Grafts of favorable axonal growth substrates were combined with transient nerve growth factor (NGF) infusions to promote morphological and functional recovery in the adult rat brain after lesions of the septohippocampal projection. Long-term septal cholinergic neuronal rescue and partial hippocampal reinnervation were achieved, resulting in partial functional recovery on a simple task assessing habituation but not on a more complex task assessing spatial reference memory. Control Neurons of the adult mammalian central nervous system (CNS) possess a limited capacity for recovery after injury (1-4). Factors that account for this limitation probably include a minimal or absent increase in neurotrophic factor levels after injury, a lack of suitable guidance channels and substrates to promote and direct axonal regrowth after injury, and the presence of growth-inhibiting molecules on CNS myelin (5). In contrast, elevation in neurotrophic factor levels (6, 7) and production of substrate molecules that promote and guide axonal growth (8-10) contribute to functionally significant axonal regeneration in the peripheral nervous system.Various substances have been grafted to the CNS to promote regeneration of host projections after injury, including peripheral nerve segments (1, 3), synthetic growth substrates (e.g., nitrocellulose, collagen gels, or amniotic membrane) (11,12), and fetal brain grafts that are utilized as "bridges" for host axonal neurite growth rather than as replacements for host neurons (13,14). In the latter instance, host fibers penetrate into and through the fetal graft to reach their host target, rather than forming synapses exclusively in the graft (13,14 MATERIALS AND METHODSThirty-eight female Fischer rats (each weighing 180 g) were anesthetized deeply, and bilateral lesions of the fimbria-fornix were made with a microscopically guided aspiration pipet. Sixteen animals then received solid grafts of embryonic-day-18 fetal hippocampal neurons to the lesion cavity, one fetal hippocampus per side of the brain. In the same session, animals received intracerebroventricular infusion devices (Alzet miniosmotic pumps) through which mouse submaxillary glandderived NGF at 100 tug/ml in artificial cerebrospinal fluid or artificial cerebrospinal fluid alone was infused at a rate of 0.25 ,ul/hr for a 9-week period. The infusion devices were then removed, and the animals were sacrificed 6 months later. Prior to sacrifice animals underwent behavioral testing (see below).

Macrophages and Microglia in Central Nervous System Injury: Are They Helpful or Harmful?

“…Similarly, regrowth was promoted by treatment with proteases that degrade chondroitin sulfate proteoglycans (Bradbury et al, 2002;Rudge and Silver, 1990). Other approaches aimed at promoting recovery of CNS axons have been based on modification of the environment by local transplantation of embryonic tissue (Grady et al, 1985), Schwann cells (Xu et al, 1997), or cells that provide a source of trophic factors to increase the survival rate of the cell bodies (Coumans et al, 2001;Tuszynski and Gage, 1995).…”

A structural basis for memory storage in mammals

“…This is highly feasible due to the high degree of plasticity demonstrated by cholinergic terminals. Following axotomy, cholinergic axons reestablish normal innervation patterns in the cerebral cortex (Farris et al, 1993), and NGF modulates the reestablishment of cholinergic ®bers and behavioral function recovery (Farris et al, 1995;Tuszynski and Gage, 1995). NGF also increases the number of varicosities, or possible release sites, along the cholinergic axon (Garofalo et al, 1993;Farris et al, 1995).…”

Liposome-mediated NGF gene transfection following neuronal injury: potential therapeutic applications

“…[1][2][3]47 NGF increases ChAT activity both in vitro 32,48 and in intact animals. 8,49 Also, intraparenchymal grafts of cells genetically modified to produce NGF can prevent cholinergic neuronal degeneration caused by fornix transection 50,51 or by immunolesioning procedures. 52 Recent studies have shown that administration of exogenous neurotrophic factors can reduce spatial memory deficits in rats following TBI.…”