Key role for pregnenolone in combination therapy that promotes recovery after spinal cord injury.

Abstract

Controlled compressive injury to rat spinal cord was chosen to test therapies that might attenuate the progression of tissue destruction and locomotor deficits that characteristically occur after spinal injury. A highly significant reduction of damage was achieved by immediate postinjury treatment with a combination of the following: an antlinflammatory substance, indomethacin; a stimulator of cytokine secretion, bacterial lipopolysaccharide; and the parent steroid, from which all other steroids arise, pregnenolone. This treatment reduced histopathological changes, spared tissue from secondary injury, and increased restoration of motor function.Remarkably, 11 of 16 of the animals treated with the above combination were able to stand and walk at 21 days after injury, 4 of them almost normally. The results were far superior to those obtained in controls or in animals to which the substances were given separately or in combinations of two. This approach may prove to be applicable to nervous system injury, in general, and to injury in other tissues.Development of a pharmacological therapy to attenuate consequences of traumatic spinal cord injuries has proven to be difficult. Such injuries trigger a characteristic selfperpetuating progression of degenerative processes that eventually result in tissue destruction and often in permanent paraplegia or quadriplegia (1-5). Any single therapy is not likely to be effective in attenuating these autodestructive processes because so many factors are involved (6-8). The key to attenuation of damage and eventual successful regeneration of injured spinal cord may lie in optimization of relations among affected neurons and surrounding nonneural cells by (i) stimulating release ofgrowth-promoting cytokines and lymphokines by nonneural cells while suppressing the effects ofcytotoxic ones, (ii) maintaining sufficient activity in injured neurons to achieve adequate genomic transcription for production of neuron-produced trophic substances, and (iii) facilitating coordinative processes that enable neural, metabolic, and immune systems, separately and together, to cycle freely through their operational modes to achieve structural and functional reconstitution.Combined treatment of rats with spinal cord injury with an antiinflammatory substance, indomethacin (IM), and a stimulator of cytokine secretion, bacterial lipopolysaccharide (LPS), reduced the amount of cavitation and increased cellular in-growth into the lesion to a greater extent than did treatment with either substance alone, but restoration of motor function was marginal (1). In the present study, we examined the effects of two steroids that have pleiotropic effects in neural and nonneural tissues, dehydroepiandrosterone sulfate (DHEAS) (9-11) and pregnenolone (PREG) (12-15), with a view to achieving further enhancement of functional recovery after injury. MATERIALS AND METHODSTest Animals and Surgical Procedures. Sprague-Dawley female rats (170-200 g) were anesthetized with 4% (wt/vol) chloral hydrate (400 mg/kg, intr...

Steroid hormones and neurosteroids in normal and pathological aging of the nervous system

“…Prevention of glucocorticoid receptor (GR) translocation into the nucleus may be involved in the observed neuroprotective effects of PREG against glutamate neurotoxicity (Gursoy et al, 2001). When administered in vivo, PREG reduced histopathological changes, saved the nervous tissue from secondary lesions and improved the recovery of motor functions after spinal cord injury (Guth et al, 1994). PREG may exert its neuroprotective effects indirectly via its conversion to PROG or by acting directly on spinal cord neurons.…”

Combining Schwann Cell Bridges and Olfactory-Ensheathing Glia Grafts with Chondroitinase Promotes Locomotor Recovery after Complete Transection of the Spinal Cord

“…Such strategies combine cell grafting with approaches including neuroprotective agents (Pearse et al, 2004b), exogenous or cellular overexpressed growth factors (Xu et al, 1995a;Bregman et al, 1997;Menei et al, 1998;Coumans et al, 2001), elevation of cAMP (Lu et al, 2004;Nikulina et al, 2004;Pearse et al, 2004a), or scar-reducing enzymes (Chau et al, 2004). Combinatory pharmacological therapies have also been tested (Guth et al, 1994;Mu et al, 2000). With regard to Schwann cell (SC) implants specifically, the addition of methylprednisolone (Chen et al, 1996), neurotrophins (Xu et al, 1995a;Menei et al, 1998;Weidner et al, 1999;Bamber et al, 2001), olfactory ensheathing glia (OEG) (Ramó n-Cueto et al, 1998), or elevated cAMP (Pearse et al, 2004a) substantially improved axonal regeneration.…”

Potentially predictive and manipulable blood serum correlates of aging in the healthy human male: Progressive decreases in bioavailable testosterone, dehydroepiandrosterone sulfate, and the ratio of insulin-like growth factor 1 to growth hormone

“…The steroidal hormones of the neuroendocrine system play multifactorial roles, acting as pleiotropic facilitators of coordinative processes that enable neural, endocrine, and metabolic systems, separately and together, to cycle freely through their operational modes in solving problems of survival and reproduction and in achieving repair and rebalancing when malfunctioning occurs (see refs. [1][2][3][4][5][6][7][8].…”