Newswise — Two studies presented at the 129th annual meeting of the American Neurological Association in Toronto describe substances that could help protect nerve cells in the spinal cord, either following injury or in neurodegenerative diseases.
One study describes a “growth factor” that can help damaged nerve fibers to grow back toward their original targets. Another demonstrates that an antibiotic called minocycline can protect nerve cells from dying when their nerve fibers have been damaged. Both studies have implications for disorders such as amyotrophic lateral sclerosis (commonly called Lou Gehrig disease in the United States), in which the spinal neurons that direct muscles degenerate and die.
Regrowing damaged nerves
The nerves that extend from the spinal cord out to muscles are actually bundles of many nerve fibers called axons, reaching out from ‘Motor’ neurons in the cord to direct muscle movement. Even when the nerve is cut or damaged, individual axons may regenerate and reattach to their targets. “Supporting cells called Schwann Cells remain in the nerve after the axons have degenerated. They secrete a variety of growth factors to help an Axon regrow back to its target tissue,” said Ahmet Hoke, MD, PhD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland.
Hoke and his colleagues recently analyzed the various substances found in damaged nerves and identified a growth factor called pleiotrophin not previously know to be secreted in by Schwann cells. Pleiotrophin has a checkered reputation: it helps the developing nervous system to grow correctly, but it also apparently helps tumor cells survive.
On October 5, 2004, at the ANA annual meeting, Hoke presented data showing that pleiotrophin helps motor Neuron axons regenerate, which in turn helps the neurons themselves survive. The potential applications go beyond helping to regenerate motor neuron axons following injury.
“There is no immediate clinical application. However, we are in the process of developing a viral delivery system for a gene therapy trial in mouse models of ALS. If successful, we could then take that technique into clinical trials,” said Hoke.
Common Antibiotic Protects Motor Neurons at High Doses
The antibiotic minocycline is no stranger to physicians. It is used to treat a variety of disorders ranging from urinary tract infections to acne. Thanks to evidence that it protects motor neurons — not to mention the fact that already has a proven safety record — minocycline is already being tested in a clinical trial of ALS patients. A study presented October 4, 2004, at the ANA meeting supports this strategy of using minocycline to protect motor neurons.
Ken Ikeda, MD, PhD, of PL Tokyo Health Care Center and the Toho University School of Medicine in Tokyo, Japan, and his colleagues gave minocycline to rats with damage to the nerves that controls muscles in the face. Typically, a portion of the motor neurons that send axons into the facial nerve will die following this injury.
Ikeda and colleagues found that minocycline added to the rats’ diet was able to protect many of the motor neurons that would otherwise have died. They also noted that minocycline appeared to prevent the activation of nearby cells called microglia, which may contribute to motor neuron decline following injury by releasing harmful molecules in the vicinity of the neurons.
The researchers mention one important difference between their study and the ALS trial in humans — the doses they employed are 10- to 20-fold higher than doses typically used in humans. Ikeda and his colleagues will repeat their experiments in rats with minocycline doses closer to the human doses, but they point out that if the current ALS trial should fail to slow the progression of the disease, it may be because the doses of the drug were too low to be effective.
[abstracts]
2. Pleiotrophin Is a Neurotrophic Factor for Motor Neurons
Ruifa Mi, Robert Huang, John W. Griffin, and Ahmet Hoke; Baltimore, MD
Background: Regeneration in the Peripheral nervous system is poor in chronically denervated nerves. Denervated Schwann cells (SCs) act as ‘presumed target’ by secreting a variety of growth factors to promote regeneration of motor and sensory axons, but loose this ability with chronic denervation.
Methods: We used focused microarrays to identify candidate neurotrophic factors secreted by denervated SCs. We examined the neurotrophic and neurotropic potential of candidate molecules using spinal cord explants in vitro and sciatic nerve regeneration paradigm in vivo.
Results: The mRNA for Pleiotrophin (PTN), a cytokine of the midkine-pleiotrophin family, was highly upregulated in acutely denervated SCs. PTN protected spinal motor neurons against chronic excitotoxic injury in a dose-dependent manner. PTN released from gelfoams and 293 cells transfected with cloned PTN caused directional outgrowth of motor axons out of the spinal cord explants and formation of “mini ventral rootlets”. Transplantation of 293 cells transfected with rat PTN into a silicone chamber allowed greater axonal regeneration after sciatic nerve transection compared to the control vector transfected 293 cells.
Summary: We have identified a new neurotrophic role for PTN. This may lead to novel treatment options for motor neuron disease.
38. Minocycline Delays Motoneuron Degeneration in an Adult Rat Model of Facial Nerve Injury
Ken Ikeda, Jo Aoyagi, Yasumitsu Ichikawa, Osamu Igarashi, Kazuhiko Watabe, Tsuyoshi Sakamoto, and Yasuo Iwasaki; Tokyo, Japan
Minocycline slows progression of motoneuron disease in mutant superoxide dismutase- transgenic mice. Our purpose is to evaluate whether this drug protects motoneurons following facial nerve avulsion of adult rats. The right facial nerve was avulsed at the stylomastoid foramen in Fischer 344 male rats (12-14 weeks old).Rats were administered 0.1 % minocycline hydrochloride or regular food for 4 weeks (each n=7). Daily intake of diet was 10-15 gm/ 100 gm of body weight and loss of food was 10-15 % during the food processing. Daily doses of minocycline were calculated as 100 mg/kg. At 4 weeks postoperation, the lower pons was stained with cresyl-violet. The number of facial motoneurons was counted and the survival ratio (the number of Lesion side/that of non-lesion side X 100 %) was determined. Immunostaining of microtubule-associated protein-2, GFAP, phospho-p44/p42 and p38 mitogen-activated protein kinase (MAPK), and isolectin B4 were done. Compared to vehicle, minocycline treatment suppressed the loss of motoneurons (P< 0.01) and preserved the neuronal network. Avulsion induced several p44/p42 MAPK-positive motoneurons. Those motoneurons and microglial activation, but not astrocytosis were inhibited in minocycline-treated rats. Our data support that minocycline attenuates motoneuron death and reduced microglia activation in facial nerve injury of adult rats. © 2004 Newswise. All Rights Reserved. Source: American Neurological Association (ANA)
