No abstract

Parkinson's disease (PD) is a neurodegenerative disease characterized by progressive degeneration of nigrostriatal dopaminergic (DA) neurons. The therapeutic potential of glial cell line-derived neurotrophic factor (GDNF), the most potent neurotrophic factor for DA neurons, has been demonstrated in many experimental models of PD. However, chronic delivery of GDNF to DA neurons in the brain remains an unmet challenge. Here, we report the effects of GDNF-releasing Notch-induced human bone marrow-derived mesenchymal stem cells (MSC) grafted into striatum of the 6-hydroxydopamine (6-OHDA) progressively lesioned rat model of PD. Human MSC, obtained from bone marrow aspirates of young, healthy adult volunteers, were transiently transfected with the intracellular domain of the Notch1 gene (NICD) to generate SB623 cells. SB623 cells expressing GDNF and/or humanized Renilla green fluorescent protein (hrGFP) following lentiviral transduction or nontransduced cells were stereotaxically placed into rat striatum 1 week after a unilateral partial 6-OHDA striatal lesion. At 4 weeks, rats that had received GDNF-transduced SB623 cells had significantly decreased amphetamine-induced rotation compared with control rats, although this effect was not observed in rats that received GFP-transduced or nontransduced SB623 cells. At 5 weeks, rejuvenated tyrosine hydroxylase-immunoreactive (TH-IR) fibers that appeared to be host DA axons were observed in and around grafts. This effect was more prominent in rats that received GDNF-secreting cells and was not observed in controls. These observations suggest that human bone-marrow derived MSC, genetically modified to secrete GDNF, hold potential as an allogeneic or autologous stem cell therapy for PD.

A majority of traumatic brain injuries (TBI) in motor vehicle crashes and sporting environments are mild and caused by high-rate acceleration of the head. For injuries caused by rotational acceleration, both magnitude and duration of the acceleration pulse were shown to influence injury outcomes. This study incorporated a unique rodent model of rotational acceleration-induced mild TBI (mTBI) to quantify independent effects of magnitude and duration on behavioral and neuroimaging outcomes. Ninety-two Sprague– Dawley rats were exposed to head rotational acceleration at peak magnitudes of 214 or 350 krad/s2 and acceleration pulse durations of 1.6 or 3.4 ms in a full factorial design. Rats underwent a series of behavioral tests including the Composite Neuroscore (CN), Elevated Plus Maze (EPM), and Morris Water Maze (MWM). Ex vivo diffusion tensor imaging (DTI) of the fixed brains was conducted to assess the effects of rotational injury on brain microstructure as revealed by the parameter fractional anisotropy (FA). While the injury did not cause significant locomotor or cognitive deficits measured with the CN and MWM, respectively, a main effect of duration was consistently observed for the EPM. Increased duration caused significantly greater activity and exploratory behaviors measured as open arm time and number of arm changes. DTI demonstrated significant effects of both magnitude and duration, with the FA of the amygdala related to both the magnitude and duration. Increased duration also caused FA changes at the interface of gray and white matter. Collectively, the findings demonstrate that the consequences of rotational acceleration mTBI were more closely associated with duration of the rotational acceleration impulse, which is often neglected as an independent factor, and highlight the need for animal models of TBI with strong biomechanical foundations to associate behavioral outcomes with brain microstructure.