Nicotine effects on regeneration?
My brother visited a doctor the other day and he said that nicotene (chew) was preventing regeneration of his spinal cord. Has anyone heard this before?
There are many studies that suggest that nicotine is deleterious to wound healing. This is because it reduces peripheral blood flow. The statement that it reduces nerve regeneration, however, was a little surprising to me and so I decided to do a literature search on the subject. I found several studies that are relevant to spinal cord injury. Let me summarize the results briefly. The abstracts are listed below.
Audesirk & Cabell (1999) reported that nicotine not only did not influence neuronal survival or neurite production but increases the branching of both axons and dendrites. Cotinine, the metabolic byproduct of nicotine, however, at relatively high concentrations of 100-1000 nM reduced neuronal survival and neurite production. Coronas, et al. (2000) found that acetylcholine (the neurotransmitter that nicotine mimics) induces neuritic outgrowth in the rat olfactory bulb.
Silverstein (1992) summarizes studies indicating that cigarete smoking delays wound healing after a variety of procedures. Cigarette smoking interferes with the healing of spinal fusions (Silicox, et al. 1995; Wing, et al. 2000) by reducing cytokine expression (Theiss, et al., 2000) , long bone fractures (Raikin, et al. 1998; Iwaniec, et al. 2001).
In summary, the data concerning nicotine suppression of axonal growth is mixed. Low doses of nicotine actually may increase neuronal survival, axonal branching and neurite outgrowth. On the other hand, several studies suggest that the nicotine byproduct cotinine reduces neuronal survival and axonal growth. However, nictine does suppress bony healing.l
• Audesirk T and Cabell L (1999). Nanomolar concentrations of nicotine and cotinine alter the development of cultured hippocampal neurons via non-acetylcholine receptor-mediated mechanisms. Neurotoxicology. 20 (4): 639-46. Summary: We investigated the effects of nicotine and its metabolic byproduct cotinine on survival, differentiation and intracellular Ca2+ levels of cultured E18 rat hippocampal neurons. We used a range of concentrations from 1 nM to 10 microM, most of which are within the likely range of human fetal exposure from maternal smoking. Nicotine did not influence neuron survival or neurite production. However, at all concentrations tested, nicotine significantly increased branching of both axons and dendrites, an effect which was not reversed by co-culturing with alpha-bungarotoxin, which blocks the nicotinic acetylcholine receptors that predominate in hippocampal cultures (Alkondon and Albuquerque, 1993; Barrantes et al., 1995b). Cotinine at 100 nM and 1 microM significantly reduced neuron survival and neurite production of surviving neurons, but did not significantly alter axon or dendrite branching. These membrane-permeable compounds may work synergistically in the developing embryo to impair the survival and differentiation of hippocampal neurons via intracellular mechanisms. Biology Department, University of Colorado at Denver, 80217-3364, USA. firstname.lastname@example.org.
• Coronas V, Durand M, Chabot JG, Jourdan F and Quirion R (2000). Acetylcholine induces neuritic outgrowth in rat primary olfactory bulb cultures. Neuroscience. 98 (2): 213-9. Summary: The rat olfactory bulb is innervated by basal forebrain cholinergic neurons and is endowed with both nicotinic and muscarinic receptors. The development of this centrifugal cholinergic innervation occurs mainly in early postnatal stages. This developmental time-course and the demonstration that acetylcholine can modulate some aspects of neuronal proliferation, differentiation or death, suggests the possible involvement of cholinergic afferents in the morphogenesis and/or plasticity of the olfactory bulb. The purpose of the present work was to assess whether acetylcholine could modulate neuronal morphogenesis in the olfactory bulb. Toward this aim, we developed a primary culture model of rat olfactory bulbs. Three major cell types were identified on the basis of their morphological and immunocytochemical phenotype: neuronal-shaped cells expressing the neuronal markers neuron specific enolase, microtubule associated protein 2, neural cell adhesion molecule and beta-tubulin III; glial-like cells immunoreactive for glial fibrillary acidic protein and flattened cells immunolabelled with antibodies against beta-tubulin III and nestin, most likely neuronal precursors. After three to six days of treatment with 100-microM carbachol, a cholinergic agonist, significant increase in neuritic length was observed in cultured olfactory bulb neurons. The neurite outgrowth effect of carbachol was abolished by co-treatment with 1 microM alpha-bungarotoxin, an alpha 7 subunit nicotinic receptor antagonist, but was not affected by the addition of 10 microM atropine, a general muscarinic antagonist. The effect of carbachol was also mimicked by the nicotinic agonists, nicotine (100 microM) and epibatidine (10 microM). This pharmacological profile suggested the involvement of nicotinic receptors of the alpha 7-like subtype as confirmed using 125I-alpha-bungarotoxin receptor autoradiography.Taken together, these data argue for a role for nicotinic receptors in neuritic outgrowth in the rat olfactory bulb and provide a cellular support to the previously described effects of acetylcholine on olfactory bulb plasticity in vivo. Douglas Hospital Research Center, Department of Psychiatry, McGill University, 6875 LaSalle Boulevard, Quebec, H4H 1R3, Verdun, Canada.
• Silverstein P (1992). Smoking and wound healing. Am J Med. 93 (1A): 22S-24S. Summary: The association between cigarette smoking and delayed wound healing is well recognized in clinical practice, although extensive controlled studies have yet to be performed. The documented effects of the toxic constituents of cigarette smoke--particularly nicotine, carbon monoxide, and hydrogen cyanide--suggest potential mechanisms by which smoking may undermine expeditious wound repair. Nicotine is a vasoconstrictor that reduces nutritional blood flow to the skin, resulting in tissue ischemia and impaired healing of injured tissue. Nicotine also increases platelet adhesiveness, raising the risk of thrombotic microvascular occlusion and tissue ischemia. In addition, proliferation of red blood cells, fibroblasts, and macrophages is reduced by nicotine. Carbon monoxide diminishes oxygen transport and metabolism, whereas hydrogen cyanide inhibits the enzyme systems necessary for oxidative metabolism and oxygen transport at the cellular level. Slower healing has been observed clinically in smokers with wounds resulting from trauma, disease, or surgical procedures. The reduced capacity for wound repair is a particular concern in patients undergoing plastic or reconstructive surgery. Compared with nonsmokers, smokers have a higher incidence of unsatisfactory healing after face-lift surgery, as well as a greater degree of complications following breast surgery. Smokers should be advised to stop smoking prior to elective surgery or when recovering from wounds resulting from trauma, disease, or emergent surgery. University of Oklahoma Health Science Center, Oklahoma City.
• Silcox DH, 3rd, Daftari T, Boden SD, Schimandle JH, Hutton WC and Whitesides TE, Jr. (1995). The effect of nicotine on spinal fusion. Spine. 20 (14): 1549-53. Summary: STUDY DESIGN. An animal model of posterior lateral intertransverse process fusion healing in the face of systemic nicotine. OBJECTIVES. To evaluate the effect of systemic nicotine on the success of spinal fusion and its effect on the biomechanic properties of a healing spinal fusion in an animal model. SUMMARY OF BACKGROUND DATA. Clinical observations suggested that cigarette smoking interferes with the healing of bony fusion. No direct link has been made to implicate nicotine as a cause for impaired healing of spinal fusions or fractures. METHODS. Twenty-eight adult female New Zealand white rabbits underwent single level lumbar posterior lateral intertransverse process fusion using autologous iliac bone graft. Animals were randomly assigned to either receive systemic nicotine or receive no nicotine. Animals were killed 35 days after surgery. Manual testing of the fusion mass was performed to determine the fusion status. Each fusion mass underwent biomechanic testing. RESULTS. Fifty-six percent of the control animals were judged to have solidly fused lumbar spines, and there were no solid fusions in the nicotine group (P = 0.02). The mean relative fusion strength in the control group was greater (P = 0.09) than in the nicotine group. For the comparable stiffness figures, the control group was greater than the nicotine group (P = 0.08). CONCLUSIONS. This animal model established a direct relationship between the development of a nonunion in the presence of systemic nicotine. The results suggested that bone formed in the face of systemic nicotine may have inferior biomechanic properties. Department of Orthopaedic Surgery, Emory University School of Medicine, Atlanta, Georgia, USA.
• Raikin SM, Landsman JC, Alexander VA, Froimson MI and Plaxton NA (1998). Effect of nicotine on the rate and strength of long bone fracture healing. Clin Orthop. (353): 231-7. Summary: Empirical clinical observation suggests that cigarette smoking had an inhibitory effect on long bone fracture healing, but this has not been proven scientifically. Forty female New Zealand White rabbits had midshaft tibial osteotomies performed and plated. These were divided randomly into two groups receiving either systemic nicotine or saline (placebo). Lateral radiographs were taken at 4, 6, and 8 weeks that showed a 17.2% average difference in callus formation between the two groups and a significant lag in formation of cortical continuity in the nicotine group. The rabbits were sacrificed 8 weeks after fracture, and healing was compared biomechanically. Three (13%) fractures showed no clinical evidence of union in the nicotine group, whereas all fractures in the control group healed. Biomechanical testing showed the nicotine exposed bones to be 26% weaker in three-point bending than were those exposed to placebo. Mount Sinai Medical Center, Department of Orthopaedic Surgery, Cleveland, OH 44106, USA.
• Wing KJ, Fisher CG, O'Connell JX and Wing PC (2000). Stopping nicotine exposure before surgery. The effect on spinal fusion in a rabbit model. Spine. 25 (1): 30-4. Summary: STUDY DESIGN: A double-blind, prospective, randomized study using a validated rabbit model of intertransverse process fusion. OBJECTIVES: To determine the effect of stopping prolonged nicotine exposure on autogenous bone graft incorporation in a rabbit lumbar spinal fusion model. SUMMARY OF BACKGROUND DATA: There is a growing body of evidence that systemic nicotine impairs healing of spinal fusions and fractures. However, it remains to be determined whether, if nicotine increases the nonunion rate of spinal fusion surgery, stopping nicotine exposure before surgery will negate this inhibitory effect. METHODS: Forty-seven rabbits were divided into two experimental groups and one control group. The two experimental groups were exposed to systemic nicotine for 8 weeks. Nicotine exposure was stopped in one group 1 week before surgery; nicotine exposure was continued in the other group throughout the study. All rabbits underwent an L5-L6 intertransverse process fusion with autogenous iliac crest bone graft. All rabbits were killed 35 days after surgery. Forty rabbits completed the study and underwent radiographic, biomechanical, and histologic testing. RESULTS: Fusion, as determined by a blinded examiner palpating the spine, occurred in 7 of 13 control rabbits, 4 of 13 rabbits that "quit" nicotine, and none of the 14 rabbits exposed to continuous nicotine. There was a statistically significant difference between the control and continuous nicotine (P = 0.0015) and between the discontinued nicotine and continuous nicotine groups (P = 0.025). Biomechanical testing showed no significant differences between groups (P = 0.11). A blinded musculoskeletal pathologist was unable to detect a difference between groups based on histologic analysis. CONCLUSIONS: Chronic nicotine exposure was shown to decrease spinal fusion rates. Discontinuing nicotine before surgery improved fusion rates. Department of Orthopaedics, University of British Columbia, Vancouver, Canada.
• Theiss SM, Boden SD, Hair G, Titus L, Morone MA and Ugbo J (2000). The effect of nicotine on gene expression during spine fusion. Spine. 25 (20): 2588-94. Summary: STUDY DESIGN: A rabbit model of posterolateral spine fusion was used to investigate the effect of nicotine on cytokine expression during spine fusion. OBJECTIVES: To determine the effects of nicotine on the known gene expression pattern of bone morphogens and related proteins expressed during spine fusion. SUMMARY OF BACKGROUND DATA: The mechanism by which nicotine increases the pseudarthrosis rate of spine fusion is unknown. Recently, a distinct temporal and spatial pattern of cytokine expression during bone formation has been described. The authors hypothesized that nicotine would alter this known pattern, thereby revealing the mechanism by which nicotine exerts its effect. METHODS: Twenty-eight New Zealand White rabbits underwent posterolateral spine fusion with autogenous bone graft. Fourteen rabbits received systemic nicotine by a miniosmotic pump. Fusions were harvested at 0, 2, 5, and 7 days and 2, 3, and 4 weeks after arthrodesis. Specimens were divided into the outer zones adjacent to the transverse processes and the central zones between the transverse processes. Gene expression of type I and II collagen, bone morphogenic protein-2, -4, and -6 and basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) was then measured at each time point in each of the two zones. RESULTS: Nicotine inhibited expression of all cytokines measured, mainly in the central zone. However, the previously described temporal and spatial patterns of expression were preserved. CONCLUSIONS: Nicotine inhibits expression of a wide range of cytokines, including those associated with neovascularization and osteoblast differentiation. Therefore, the effects of nicotine appear to involve more than just local vasoconstriction. Division of Orthopedic Surgery, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA. Steven.Theiss@ortho.uab.edu.
• Iwaniec UT, Fung YK, Akhter MP, Haven MC, Nespor S, Haynatzki GR and Cullen DM (2001). Effects of nicotine on bone mass, turnover, and strength in adult female rats. Calcif Tissue Int. 68 (6): 358-64. Summary: This study investigated the effects of nicotine, the chemical responsible for tobacco addiction, on bone and on serum mineral and calcitropic hormone levels in adult, female rats to help resolve a current controversy regarding the impact of nicotine on bone health. Seven-month-old rats received either saline (n = 12), low-dose nicotine (4.5 mg/kg/day, n = 2), or high-dose nicotine (6.0 mg/kg/day, n = 12) administered subcutaneously via osmotic minipumps for 3 months. Blood, femora, tibiae, and lumbar vertebrae (3-5) were collected at necropsy for determination of serum mineral and hormonal concentrations, bone density (femora and vertebrae), bone turnover (tibiae), and bone strength (femora). The presence of nicotine in serum (111 +/- 7 and 137 +/- 10 ng/ml for the low- and high-dose nicotine groups, respectively) confirmed successful delivery of the drug via osmotic minipumps. Nicotine-induced treatment differences were not detected in serum calcium, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D. However, serum phosphorus and parathyroid hormone (PTH) were higher in rats treated with high-dose nicotine, and serum calcitonin was lower in rats treated with both high- and low-dose nicotine than in control rats. Nicotine treatment had no effect on tibial cancellous or cortical bone turnover or femoral bone mineral content (BMC) and density (BMD). Femoral ultimate load and vertebral BMC were lower in rats treated with high-dose nicotine than in control rats. We conclude that nicotine at serum concentrations 2.5-fold greater than the average in smokers has limited detrimental effects on bone in normal, healthy female rats. Osteoporosis Research Center, Creighton University, Omaha, Nebraska, 68131, USA.
I don't know if this means anything, but prior to injury I chewed tobacco for about 5 years. Now when I try some it makes everything below the injury burn and tingle like mad. Could this be a real response or just "in my head" like so many other people have said about phantom sensations?
Here's my two cents on the subject. I have been dipping copenhagen snuff the whole 29 years of my injury: about a can a day. A recent blood test revealed I have a very high level on nicotine in my system. As far as stopping regeneration, I really have my doubts, because I have had alot of return over the years with my injury. Never smoked and never will. I do believe inhaling smoke is stupid and the most harmful thing anyone could do their body.
I think this somehow related
Cigarettes, Tea Linked to Lower Parkinson's Risk
Fri Apr 19, 5:56 PM ET
NEW YORK (Reuters Health) - New research provides more evidence of the unusual link between smoking and a lower risk of Parkinson's disease (news - web sites).
But far from recommending smoking as a way to reduce Parkinson's risk, researchers point out that understanding the relationship could help identify the cause of the disease and ways to treat or prevent it.
Parkinson's disease is marked by the loss of brain cells that produce the chemical dopamine, leading to symptoms such as tremor, rigidity and stiffness, slowed movement and problems with balance and coordination. The exact cause is unknown, but many researchers believe that a combination of environmental factors, genetics and aging are at work.
For the past three decades, various studies have linked smoking to lower Parkinson's disease risk, according to the authors of the new study. But a biological explanation for the connection has remained elusive, and some researchers have suggested that smoking itself is not protective. Rather, they say, some genetic characteristics may underlie both Parkinson's and the tendency to smoke.
In the current investigation, Dr. Harvey Checkoway and his colleagues at the University of Washington in Seattle studied the relationship between Parkinson's and cigarette smoking, alcohol and caffeine consumption in 210 men and women diagnosed with Parkinson's disease, and 310 men and women without the disease.
After analyzing questionnaires completed by all the participants, the researchers found that smokers had a 50% lower risk of Parkinson's disease, and current smokers had a 70% lower risk than ex-smokers.
"No associations were detected for coffee consumption or total caffeine intake or for alcohol consumption," Checkoway and colleagues write in the April issue of the American Journal of Epidemiology.
"However, reduced risks were observed for consumption of two cups per day or more of tea and two or more cola drinks per day," the authors add.
What the possible mechanisms are for these interactions--or even if the relationships are truly cause-and-effect--are unknown. With regard to smoking, one hypothesis, the researchers note, is that cigarette smoke protects against Parkinson's by inhibiting certain enzymes that can have toxic effects on brain cells. Some speculate, based on animal research, that nicotine helps protect brain cells.
SOURCE: American Journal of Epidemiology 2002;155:732-738.
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People with early stage Parkinson's disease are very sensitive to nicotine because one of the ways in which they compensate for the decrease in dopaminergic innervation is to boost their acetylcholine receptors sensitivity. Since nicotine acts on the acetylcholine receptor, these people are very sensitive to nicotine. The relationship between smoking (as well as tea/coffee) and Parkinson's disease has long been known. Likewise, farmers with early Parkinson's disease are very sensitive to insecticides that block acetylcholinesterase (the enzyme that breaks down acetylcholine). These effects are believed to be an effect of the compensatory mechanisms that people with Parkinson's diseases utilize to compensate.