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Brain research (1)
Rothstein, Jeffrey D. (2)
Bartus, Raymond T. (1)
Bishop, Kathie M. (1)
DeLeo, Joyce A. (1)
Gasmi, Mehdi (1)
LaCroix-Fralish, Michael L. (1)
Lepore, Angelo C. (1)
Maragakis, Nicholas J. (1)
Nutile-McMenemy, Nancy (1)
Perez, Natalie (1)
Regan, Melissa R. (1)
Tawfik, Vivianne L. (1)
Year of Publication
Intraparenchymal spinal cord delivery of adeno-associated virus IGF-1 is protective in the SOD1G93A model of ALS
Lepore, Angelo C.
Bishop, Kathie M.
Bartus, Raymond T.
Maragakis, Nicholas J.
The potent neuroprotective activities of neurotrophic factors, including insulin-like growth factor 1 (IGF-1), make them promising candidates for treatment of amyotrophic lateral sclerosis (ALS). In an effort to maximize rate of motor neuron transduction, achieve high levels of spinal IGF-1, and thus enhance therapeutic benefit, we injected an adeno-associated virus 2 (AAV2)-based vector encoding human IGF-1 (CERE-130) into lumbar spinal cord parenchyma of SOD1G93A mice. We observed robust and long-term intraspinal IGF-1 expression and partial rescue of lumbar spinal cord motor neurons, as well as sex-specific delayed disease onset, weight loss, decline in hindlimb grip strength and increased animal survival.
Adeno; associated virus; insulin; like growth factor 1; gene therapy; neurodegeneration; amyotrophic lateral sclerosis; neuroprotection
Propentofylline-Induced Astrocyte Modulation Leads to Alterations in Glial Glutamate Promoter Activation Following Spinal Nerve Transection
Tawfik, Vivianne L.
Regan, Melissa R.
LaCroix-Fralish, Michael L.
DeLeo, Joyce A.
We have previously shown that the atypical methylxanthine, propentofylline, reduces mechanical allodynia after peripheral nerve transection in a rodent model of neuropathy. In the present study, we sought to determine whether propentofylline-induced glial modulation alters spinal glutamate transporters, GLT-1 and GLAST in vivo, which may contribute to reduced behavioral hypersensitivity after nerve injury. In order to specifically examine the expression of the spinal glutamate transporters, a novel line of double transgenic GLT-1-eGFP/GLAST-DsRed promoter mice was used. Adult mice received propentofylline (10 mg/kg) or saline via intraperitoneal injection starting 1-hour prior to L5-spinal nerve transection and then daily for 12 days. Mice receiving saline exhibited punctate expression of both eGFP (GLT-1 promoter activation) and DsRed (GLAST promoter activation) in the dorsal horn of the spinal cord, which was decreased ipsilateral to nerve injury on day 12. Propentofylline administration reinstated promoter activation on the injured side as evidenced by an equal number of eGFP (GLT-1) and DsRed (GLAST) puncta in both dorsal horns. As demonstrated in previous studies, propentofylline induced a concomitant reversal of L5 spinal nerve transection-induced expression of Glial Fibrillary Acidic Protein (GFAP). The ability of propentofylline to alter glial glutamate transporters highlights the importance of controlling aberrant glial activation in neuropathic pain and suggests one possible mechanism for the anti-allodynic action of this drug.
Spinal glia; Neuropathic pain; Neuroimmune; Peripheral nerve injury; Mice
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