INTRODUCTION:

The nervous system responds rapidly to variation in your external and internal environment. It works with the endocrine system and together they control major homeostatic functions (maintenance of a stable internal environment in the body). There are three basic functions of the nervous system: It receives stimuli from the external and internal environments, It will analyse and interpret information, It initiates an appropriate and co-ordinated response. There are two principal parts are -1)The central nervous system (CNS) is the brain and spinal cord. Incoming sensory information reaches the brain via spinal and cranial nerves. The brain then sorts it all out and stores memories and issues instructions. The CNS controls most muscle contraction and glandular secretions. 2) The peripheral nervous system (PNS) receives information from the periphery of the body, such as the skin, as well as deeper organs and tissues and the special senses such as sight and hearing. There are input and output routes. Parts of the nervous system are under voluntary control, but most nerve responses are involuntary.

When damage to nervous system occurs, neuroregeneration comes into play. Neuroregeneration refers to the regrowth or repair of nervous tissues, cells or cell products. When an axon is damaged, the distal segment undergoes Wallerian degeneration, losing its myelin sheath. The proximal segment can either die by apoptosis or undergo the chromatolytic reaction, which is an attempt at repair. In the CNS, synaptic stripping occurs as glia foot processes invade the dead synapse.^[1]

VARIOUS METHODS OF NEURAL REGENERATION:

v AYURVEDHIC

v ALLOPATHIC

v NATURAL

v STEM CELL

AYURVEDHIC METHOS:

Ayurveda remains one of the most ancient and yet living traditions practiced widely in India, Sri Lanka and other countries and has a sound philosophical and experiential basis. In conclusion, Ayurvedic medicine represents an ancient healthcare tradition that is becoming increasingly popular as an alternative medicine modality. Its emphasis on health maintenance through enhancing inherent healing ability has considerable relevance for many chronic health problems, including those that frequently afflict people with spinal cord injury and dysfunction. Ayurveda physiology explains a dynamic exchange between in terms of continuous regeneration of tissues. The tissues undergo continuous process of destruction and regeneration. The homeostasis is maintained by Doshas, those regulate all the metabolic processes. Vata regulates the catabolic activity (tissue wear and tear), Kapha stimulates synthesis of newer tissues, and Pitta governs the process of nutrients assimilation into tissues. Dosha act through body tissue, Ayurveda terms those as Dhatus (Sanskrit meaning to hold or withstand). Ayurveda recommends several dietary, lifestyle, and herbomineral interventions for Dosha balance and Dhatu nourishment resulting in healthy long life. Traditionally therapies such as Panchakarma and Rasayana are used in Ayurveda for rejuvenation. Current knowledge on adult and embryonic stem cells if used along with concepts of regeneration in Ayurveda can contribute to the development of regenerative medicine with integrative approach.[2]

Ayurveda, the traditional Indian medicine (TIM), and traditional Chinese medicine (TCM) remain the most ancient yet living traditions.[3] Scientific studies on Ayurvedic botanicals and Chinese herbs have shown to be effective in degenerative diseases such as arthritis, Parkinson's disease, and Alzheimer's disease.[4,5,6] The tissue protective effects of Rasayana herbs are known. For example, chondroprotective activity of Phyllanthusemblica inhibiting the activities of hyaluronidase and collagenase type 2 in vitro.[7] Phyllanthusemblica fruits, Shorearobusta resin, and Yashadabhasma have shown activities in wound healing, fractures, anemia, corneal ulcers, brain, and deoxyribonucleic acid (DNA) damage in experimental models.[8] Amalaki Rasayana (a preparation of Amla fruits-Phyllanthusemblica) has effectively demonstrated reduction in DNA damage in brain cells demonstrating its genomic stability in neurons and astrocytes.[9] The same formulation demonstrated increase in median lifespan and starvation resistance in Drosophila melanogaster mode.[10] Several formulations of Ayurveda are used for growth, healthy aging, and arresting degeneration. A recent study on one of such formulations, Dhanvantar Kashaya (a decoction of herbs having regeneration property) has demonstrated activity on Wharton jelly mesenchymal stem cells (WJMSCs). The decoction increased the proliferation rate, decreased the turnover time, and also delayed senescence. Ayurvedic formulation, Dhanwantram Kashaya, used as a growth enhancer, is able to improve the yield and quality of stem cells in vitro and could be an effective nontoxic supplement for culturing WJMSCs for clinical applications.[11]Curcumin had been demonstrated to stimulate developmental and adult hippocampal neurogenesis, and a biological activity that may enhance neural plasticity and repair.[12]Traditional Chinese medicinal composition for promoting bone marrow-derived MSC survival in vivo is reported. This composition is shown to promote differentiation into cardiomyocytes lineage.[13] Zuo et al.,[14] has reported that Panax ginseng induced K562 cells to differentiate into erythrocytes. In addition, other groups demonstrated that treatment with herbal extract enhanced the contractility of embryonic stem cell-derived cardiomyocytes. Sasaki et al.,[15] demonstrated that treatment with a Panax ginseng compound promoted the differentiation of mouse embryonic stem cells into cardiomyocytes. Lam et al.,[16] described in detail the mechanisms by which a four-herb Chinese medicine formula reduces chemotherapy-induced gastrointestinal toxicity. This formula acts at the level of the gastrointestinal progenitor and stem cells. The herbal compound PHY906 appeared to be responsible. It induced the expression of the stem cell markers CD44, Lgr5, Ascl2, and Olfm4 and increased the expression of Wnt signaling components 4 days after CPT-11 chemotherapy. These results suggest that PHY906 may promote progenitor cell regeneration after CPT-11 treatment by stimulating Wnt signaling. Sheng et al.,[17] reported that the novel semisynthetic molecule icaritin, based on a common metabolite of seven flavonoid glycosides derived from herb Epimedium could stimulate osteogenic differentiation and inhibit adipogenesis of MSCs, which was associated with the suppression of GSK3β and PPARγ.

Ginkgo biloba extract was shown to promote proliferation of endogenous neural stem cells in vascular dementia rats.[18] Natural compounds from traditional Chinese herbal medicines, which are extensively used in China to treat stroke clinically and tested their proliferation-inducing activities on neural stem/progenitor cells (NSPCs). The screening results showed that salvianolic acid B (Sal B) displayed marked effects on the induction of proliferation of NSPCs.[19] Baicalin, a flavonoid compound isolated from Scutellariabaicalensis. The effect of baicalin was observed in E15–16 embryonic neural precursor cells (NPCs), in which it promoted neural differentiation but inhibited glial formation by regulating expression of stat3 and bHLH.[20] Chen et al.,[21] observed the effect of (+)-cholesten-3-one, which was purified from Plastrumte studinis in TCM. (+)-Cholesten-3-one can effectively promote the activity of tyrosine hydroxylase (TH) promoter of P19 cells depending on bone morphogenetic protein (BMP) signaling. Phenotypic cellular analysis also indicated that it induces differentiation of NSCs to dopaminergic neurons with increased expression of TH, dopamine transporter (DAT), dopamine decarboxylase, and higher level of dopamine secretion.

ALLOPATHIC METHODS:

Regenerative medicine has entered a new era with the development of modern science and technology. Joseph P. Steiner and et al showed that the nonimmunosuppressive analogues of the immunosuppressive drugs FK506, rapamycin and cyclosporin A promote neurite outgrowth both in PC12 cells and sensory neu-ronal cultures of dorsal root ganglia with potencies resembling their immunosuppressive homologues. Neurotrophic potencies of the immunophilin ligands resemble their potencies in binding to and inhibiting the rotamase activity of FKBP-12 or cyclophilin. Since nonimmunosuppressive immunophilin ligands, which are devoid of calcineurin inhibitory activity, are equally neurotrophic, inhibition of calcineurin activity is not the mediator of the neurotrophic effects. The immunophilin ligands are neurotrophic in intact animals. FK506 and L-685,818 (the C18-hydroxy, C21-ethyl derivative of FK506) treatment of rats with crushed sciatic nerves enhances both functional and morphologic recovery. The striking potency of these agents, their bioavailability and the dissociation of neurotrophic from immunosuppressant actions argue for their therapeutic relevance in the treatment of neurodegenerative diseases [22]. FK506 is a new FDA-approved immunosuppressant used for prevention of allograft rejection in, for example, liver and kidney transplantations. FK506 is inactive by itself and requires binding to an FK506 binding protein-12 (FKBP-12), or immunophilin, for activation. In this regard, FK506 is analogous to cyclosporin A, which must bind to its immunophilin (cyclophilin A) to display activity. This FK506-FKBP complex inhibits the activity of the serine/threonine protein phosphatase 2B (calcineurin), the basis for the immunosuppressant action of FK506. The discovery that immunophilins are also present in the nervous system introduces a new level of complexity in the regulation of neuronal function. Two important calcineurin targets in brain are the growth-associated protein GAP-43 and nitric oxide (NO) synthase (NOS).Taken together; studies of FK506 indicate broad functional roles for the immunophilins in the nervous system. Both calcineurin-dependent (e.g., neuroprotection via reduced NO formation) and calcineurin-independent mechanisms (i.e., nerve regeneration) need to be invoked to explain the many different neuronal effects of FK506. This suggests that multiple immunophilins mediate FK506's neuronal effects. Novel, nonimmunosuppressant ligands for FKBPs may represent important new drugs for the treatment of a variety of neurological disorders.[24]

Chitosan can be obtained by alkaline deacetylation of chitin and is found to be a natural-based nontoxic, biocompatible, and biodegradable polymer with anti-microbial activity. Chitosan and its derivatives could accelerate wound healing by enhancing the functions of inflammatory cells and repairing cells. Recent studies further indicated that chitosan and its derivatives also are novel scaffold materials for tissue engineering and are-promising non-viral vectors for gene delivery. The novel properties of chitosan make it a versatile biomaterial for cell therapy, tissue engineering and gene therapy. It is hoped that these diverse approaches for regenerative medicine will translate from “bench to bedside” in the future.[23]

Insulin-like growth factor-I (IGFI) receptors are present in the spinal cord, and, like members of the neurotrophin receptor family, IGF-I receptors mediate signal transduction via a tyrosine kinase domain. IGF-I was found to prevent the loss of choline acetyltransferase activity in embryonic spinal cord cultures, as well as to reduce the programmed cell death of motor neurons in vivo during normal development or following axotomy or spinal transection. Consistent with earlier reports that IGF-I enhances motor neuronal sprouting in vivo, subcutaneous administration of IGF-I increases muscle endplate size in rats. Subcutaneous injections of IGF-I also accelerate functional recovery following sciatic nerve crush in mice, as well as attenuate the peripheral motor neuropathy induced by chronic administration of the cancer chemotherapeutic agent vincristine in mice. Doses of IGF-I that accelerate recovery from sciatic nerve crush in mice result in elevated serum levels of IGF-I which are similar to those obtained following subcutaneous injections of formulated recombinant human IGF-I (Myotrophin) in normal human subjects. Based on these findings, together with evidence of safety in animals and man, clinical trials of recombinant human IGF-I have been initiated in patients with amyotrophic lateral sclerosis and are planned to begin soon in patients with chemotherapy-induced peripheral neuropathies.[25]

NATURAL METHODS:

Animal-Based Omega-3 Fats:

Docosahexaenoic acid an omega-3 fat is an essential structural component of both brain and retina. Approximately 60 percent of brain is composed of fats—25 percent of which is DHA. DHA is also an essential structural ingredient of breast milk, which is believed to be a major reason why breastfed babies consistently score higher on IQ tests than formula-fed babies.Omega-3 fats such as DHA are considered essential because body cannot produce it, and must get it from daily diet. DHA-rich foods include fish, liver, and brain. DHA is found in high levels in neurons -- the cells of central nervous system, where it provides structural support. When omega-3 intake is inadequate, your nerve cells become stiff and more prone to inflammation as the missing omega-3 fats are substituted with cholesterol and omega-6 instead. Once your nerve cells become rigid and inflamed proper neurotransmission from cell to cell and within cells become compromised. The influence of omega-3 fat on physical and mental health has been the subject of intense research over the last four decades, and there's compelling evidence that animal-based omega-3 fats can help reduce the symptoms of a variety of psychiatric illnesses and degenerative brain disorders. For example, low DHA levels have been linked to memory loss and Alzheimer's disease.

Even more exciting is research showing that degenerative conditions can not only be prevented but also potentially reversed. For example, in one study, 485 elderly volunteers suffering from memory deficits saw significant improvement after taking 900 mg of DHA per day for 24 weeks, compared with controls.[27] Another study found significant improvement in verbal fluency scores after taking 800 mg of DHA per day for four months compared with placebo.[28]Furthermore, memory and rate of learning were significantly improved when DHA was combined with 12 mg of lutein per day. Interestingly, research suggests that the unsaturated fatty acid composition of normal brain tissue is age-specific, which could imply that the older you get, To compensate for our inherently low omega-3 diet, a high quality animal-based omega-3 supplement is something that is recommend for virtually everyone, especially if pregnant. Krill oil is as effective as fish oil despite the fact that it contains less EPA and DHA. This is because krill oil is absorbed up to 10-15 times as well as fish oil, due to its molecular composition, and is less prone to oxidation (rancidity) because it is naturally complexed with the potent fat-soluble antioxidant astaxanthin.

Vitamin B12:

Recent research has bolstered the importance of this vitamin in keeping our mind sharp as we age. According to the latest research, people with high levels of markers for vitamin B12 deficiency were more likely to score lower on cognitive tests, as well as have a smaller total brain volume, [31] which suggests a lack of the vitamin may contribute to brain shrinkage. Mental fogginess and problems with memory are two of the top warning signs that occur in vitamin B12 deficiency. In addition, a Finnish study found that people who consume foods rich in B12 may reduce their risk of Alzheimer's in their later years. [32] For each unit increase in the marker of vitamin B12 (holotranscobalamin) the risk of developing Alzheimer's was reduced by 2 percent. Research also shows that supplementing with B vitamins, including B12, helps to slow brain atrophy in elderly people with mild cognitive impairment (brain atrophy is a well-established characteristic of Alzheimer's disease). B12 is available in its natural form only in animal food sources. These include seafood, beef, chicken, pork, milk, and eggs. Now recommend an under-the-tongue fine mist spray, as this technology helps us to absorb the vitamin into the fine capillaries under your tongue.

Vitamin D:

Activated vitamin D receptors increase nerve growth in your brain, and researchers have also located metabolic pathways for vitamin D in the hippocampus and cerebellum of the brain, areas that are involved in planning, processing of information, and the formation of new memories. The National Institutes of Mental Health recently concluded that it is vital that the mother get enough vitamin D while pregnant in order for the baby's brain to develop properly. The child must also get enough vitamin D after birth for "normal" brain functioning. In older adults, too, research has shown that low vitamin D levels are associated with poorer brain function, and increasing levels may help keep older adults mentally fit. [30] Appropriate sun exposure would take care of these issues, as the sun is irreplaceable when it comes to the body's ability to produce adequate amounts of vitamin D.

Coconut Oil:

One of the primary fuels our brain need is glucose, which is converted into energy. Our brain actually manufactures its own insulin to convert glucose in our bloodstream into the food it needs to survive. If our brain's production of insulin decreases, your brain literally begins to starve, as it's deprived of the glucose-converted energy it needs to function normally. This is what happens to Alzheimer's patients -- portions of their brain start to atrophy, or starve, leading to impaired functioning and eventual loss of memory, speech, movement and personality. There's another substance that can feed our brain and prevent brain atrophy. It may even restore and renew neuron and nerve function in our brain after damage has set in. The substance in question is called ketone bodies or ketoacids. Ketones are what your body produces when it converts fat (as opposed to glucose) into energy, and a primary source of ketone bodies are the medium chain triglycerides (MCT) found in coconut oil! Coconut oil contains about 66 percent MCTs. Therapeutic levels of MCTs have been studied at 20 grams per day. Coconut oil is best taken with food, to avoid upsetting our stomach.

STEM CELL METHOD:

Stem cell research is being pursued in the hope of achieving major medical breakthroughs in treatment of diseases. Stem cells are self-renewing, unspecialized cells that can give rise to multiple cell types of all tissues of the body. Somatic or adult stem cells typically generate the cell types of the tissue in which they reside. For example, a blood-forming adult stem cell in the bone marrow normally gives rise to the many types of blood cells. It is generally accepted that a blood-forming cell in the bone marrow—which is called a hematopoietic stem cell—cannot give rise to the cells of a very different tissue, such as nerve cells in the brain. Experiments over the last several years have purported to show that stem cells from one tissue may give rise to cell types of a completely different tissue, a phenomenon known as plasticity. Examples of such plasticity include blood cells becoming neurons, liver cells that can be made to produce insulin, and hematopoietic stem cells that can develop into heart muscle. Therefore, exploring the possibility of using adult stem cells for cell-based therapies has become a very active research area. [35]

In recent years, several lines of evidence have suggested that adult stem cells are multipotent and can differentiate into different cell lineages. Adult bone marrow, brain, liver, pancreas, fat, skin, and skeletal muscle, have all been shown to possess stem or progenitor cells with the capacity to differentiate into cell types other than their tissue of origin.

Studies with bone marrow stromal or MSCs, a subset of cells that can be separated by plastic adherence, have shown differentiation into various cell types, including bone,[36,37] tendon, cartilage, and fat.[38] Stem cells, directed to differentiate into specific cell types, offer the possibility of a renewable source of replacement cells and tissues to treat diseases including Parkinson's and Alzheimer's diseases, spinal cord injury, stroke, burns, heart disease, diabetes, osteoarthritis, and rheumatoid arthritis.[39]

The recent availability of human ES cells has led to further studies to examine their potential for differentiation into dopamine neurons. Recently, dopamine neurons from human embryonic stem cells have been generated.[41] One research group used a special type of companion cell, along with specific growth factors, to promote the differentiation of the ES cells through several stages into dopamine neurons. These neurons showed many of the characteristic properties of normal dopamine neurons.[41] Furthermore, recent evidence of more direct neuronal differentiation methods from mouse ES cells fuels hope that scientists can refine and streamline the production of transplantable human dopamine neurons. One method with great therapeutic potential is nuclear transfer. This method fuses the genetic material from one individual donor with a recipient egg cell that has had its nucleus removed. The early embryo that develops from this fusion is a genetic match for the donor. This process is sometimes called quot; therapeutic cloningquot; and is regarded by some to be ethically questionable. However, mouse ES cells have been differentiated successfully in this way into dopamine neurons that corrected Parkinsonian symptoms when transplanted into 6-OHDA-treated rats.[42] Similar results have been obtained using parthenogenetic primate stem cells, which are cells that are genetic matches from a female donor with no contribution from a male donor.[43] These approaches may offer the possibility of treating patients with genetically-matched cells, thereby eliminating the possibility of graft rejection.[40]

REFFERENCE:

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15. Sasaki T, Oh KB, Matsuoka H, Saito M. Effect of Panax ginseng components on the differentiation of mouse embryonic stem cells into cardiac-like cells. YakugakuZasshi. 2008; 128:461–7.

16. Lam W, Bussom S, Guan F, Jiang Z, Zhang W, Gullen EA, et al. The four-herb Chinese medicine PHY906 reduces chemotherapy-induced gastrointestinal toxicity. SciTransl Med. 2010; 2:45ra59.

17. Sheng H, Rui XF, Sheng CJ, Li WJ, Cheng XY, Jhummon NP. A novel semisynthetic molecule icaritin stimulates osteogenic differentiation and inhibits adipogenesis of mesenchymal stem cells. Int J Med Sci.2013; 10:782–9.

18. Wang JW, Chen W, Wang YL. A Ginkgo biloba extract promotes proliferation of endogenous neural stem cells in vascular dementia rats. Neural Regenerat Res. 2013; 8:1655–62.

19. Zhuang P, Zhang Y, Cui G, Bian Y, Zhang M, Zhang J, et al. Direct stimulation of adult neural stem/progenitor cells in vitro and neurogenesis in vivo by salvianolic acid B. PLoS One. 2012; 7:e35636.

20. Li Y, Zhuang P, Shen B, Zhang YJ, Shen J. Baicalin promotes neuronal differentiation of neural stem/progenitor cells through modulating p-stat3 and bHLH family protein expression. Brain Res.2012; 1429:36–42.

21. Chen DF, Meng LJ, Du SH, Zhang HL, Li H, Zhou JH, et al. (+)-Cholesten-3-one induces differentiation of neural stem cells into dopaminergic neurons through BMP signaling. Neurosci Res.2010; 68:176–84.

22. Neurotrophic actions of nonimmunosuppressive analogues of immunosuppressive drugs FK506, rapamycin and cyclosporinAJoseph P. Steiner1, Maureen A. Connolly1, Heather L. Valentine1, Gregory S. Hamilton2, Ted M. Dawson3, 4, Lynda Hester3 and Solomon H. Snyder3. Nature Medicine 3, 421 - 428 (1997) .

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30. Association between 25-hydroxyvitamin D levels and cognitive performance in middle-aged and older European men. Lee DM¹, Tajar A, Ulubaev A, Pendleton N, O'Neill TW, O'Connor DB, Bartfai G, Boonen S, Bouillon R, Casanueva FF, Finn JD, Forti G, Giwercman A, Han TS, Huhtaniemi IT, Kula K, Lean ME, Punab M, Silman AJ, Vanderschueren D, Wu FC; EMAS study group. J Neurol Neurosurg Psychiatry. 2009 Jul; 80(7):722-9. doi: 10.1136/jnnp.2008.165720. Epub 2009 May 21.

31. Vitamin B12, cognition, and brain MRI measures: a cross-sectional examination. Tangney CC¹, Aggarwal NT, Li H, Wilson RS, Decarli C, Evans DA, Morris MC.Neurology. 2011 Sep 27; 77(13):1276-82. doi: 10.1212/WNL.0b013e3182315a33.

32. Beauty and the beast: B12, homocysteine, and the brain: a bemusing saga! Seshadri S. Neurology. 2010 Oct 19; 75(16):1402-3. doi: 10.1212/WNL.0b013e3181f8836f.

33. Metabolic effects of krill oil are essentially similar to those of fish oil but at lower dose of EPA and DHA, in healthy volunteers.Ulven SM¹, Kirkhus B, Lamglait A, Basu S, Elind E, Haider T, Berge K, Vik H, Pedersen JI. Lipids. 2011 Jan; 46(1):37-46. doi: 10.1007/s11745-010-3490-4. Epub 2010 Nov 2.

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40. Repairing the Nervous System with Stem Cells, David M. Panchision

41. Perrier AL, Tabar V, Barberi T, et al. Derivation of midbrain dopamine neurons from human embryonic stem cells. ProcNatlAcadSci USA. 2004; 101:12543–12548.

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Received on 16.05.2015 Modified on 19.06.2016

Research J. Pharm. and Tech 2017; 10(12): 4423-4428.

DOI: 10.5958/0974-360X.2017.00815.0

27. Beneficial effects of docosahexaenoic acid on cognition in age-related cognitive decline. Yurko-Mauro K1, McCarthy D, Rom D, Nelson EB, Ryan AS, Blackwell A, Salem N Jr, Stedman M; MIDAS Investigators. Alzheimers Dement. 2010 Nov; 6(6):456-64. doi: 10.1016/j.jalz.2010.01.013.

31. Vitamin B12, cognition, and brain MRI measures: a cross-sectional examination. Tangney CC1, Aggarwal NT, Li H, Wilson RS, Decarli C, Evans DA, Morris MC.Neurology. 2011 Sep 27; 77(13):1276-82. doi: 10.1212/WNL.0b013e3182315a33.

32. Beauty and the beast: B12, homocysteine, and the brain: a bemusing saga! Seshadri S. Neurology. 2010 Oct 19; 75(16):1402-3. doi: 10.1212/WNL.0b013e3181f8836f.

27. Beneficial effects of docosahexaenoic acid on cognition in age-related cognitive decline. Yurko-Mauro K¹, McCarthy D, Rom D, Nelson EB, Ryan AS, Blackwell A, Salem N Jr, Stedman M; MIDAS Investigators. Alzheimers Dement. 2010 Nov; 6(6):456-64. doi: 10.1016/j.jalz.2010.01.013.

31. Vitamin B12, cognition, and brain MRI measures: a cross-sectional examination. Tangney CC¹, Aggarwal NT, Li H, Wilson RS, Decarli C, Evans DA, Morris MC.Neurology. 2011 Sep 27; 77(13):1276-82. doi: 10.1212/WNL.0b013e3182315a33.