INTRODUCTION:

Bacopa monnieri or Brahmi is a beneficial medicinal plant that enhances memory and cognition. It is a small perennial creeping herb in the Scrophulariaceae family, which includes 220 genera. The name Brahmi is taken from the Hindu pantheon's legendary "builder" and "Bramai." The plant has a soft stem that is between 10-30cm long and 1-2mm thick. Sessile, succulent, and oppositely arranged on the stem, the leaves are 0.6 - 2.5 cm long and 0.2-1cm thick. Owing to the existence of many substances such as alkaloids, saponins, glycosides, flavonoids, and stigma-sterols, it has a variety of pharmacological actions¹. Bacoside A and B are two main chemicals (saponin in nature) present in Brahmi.

Bacoside A is the main ingredient answerable for the memory-boosting effect. Bacoside A and Bacoside B vary in optical rotation, with Bacoside A being levorotatory structure and Bacoside B being dextrorotatory arrangement. Several pharmacological activities have been reported of this plant constituents. The chemical ingredients of Brahmi play their important biological role in cancer, neuro disease, cardiac disease, gastrointestinal system, and blood sugar level. Donepezil, Rivastigmine, Galantamine and Memantine are mostly prescribed medications for the treatment of AD. But in case of the meantime, only about 20% of AD patients respond moderately to these medications, with benefits lasting six to twelve months on average, and sometimes with severe adverse effects. As a result, more successful pharmacological treatments with less side effects must be developed and evaluated urgently. Plant BM which is used as herb in Ayurvedic medicine contain Bacoside A and Bacoside B which has potential as therapeutic agent for AD. In this review paper, we are trying to focus on the specific effects of Brahmi on cholinergic system, amyloid beta protein related to nervous system as well as diabetic neuropathy.

Chemical Composition of BM:

Bacoside A, bacoside B, monnierin are three major saponin present in this tree. These are dammarane type triterpenoid saponins. Other than these chemicals Apigenin, Brahmine, and Asiaticoside are also present which are belonging to flavonoids, alkaloids, and glycoside class. Among these biologically active constituents saponins are having the potent pharmacological effectiveness. Bacoside-A along with bacopaside-I possess more than 96% w/w of the total saponins of Brahmi^2,3,4.

The structures of the chemical compositions are as follows (Figure 1-4)

Figure 1: Bacoside A Figure 2: Bacoside B

Figure 3: Apigenin Figure 4: Asiaticoside.

Brief Attention on Several Pharmacological Activities of Brahmi:

Besides neuronal activities, Ayurvedic data also states the usefulness of BM in other physiological conditions⁵. Several researchers have explained as following in Figure 5-

Figure. 5- Several therapeutically effectiveness of Brahmi.

Brief Attention on AD:

It is the utmost prevalent form of dementia, as it is a neuron-degenerative disease of an unknown cause. The type of N-methyl-D-aspartate receptor (NMDA) is glutamate receptor. NMDA receptor plays a pivotal role to control synaptic plasticity and brain function. N-methyl-D-aspartate binds selectively to the ion channel type of receptor (NMDA receptor), that is why the NMDA receptor is so named, which is one inotropic glutamate receptor^6-11. The cells of the brain are affected due to Alzheimer disease resulting intellectual functioning are lessened. Loss of memory, senile dementia, intra-neuronal neuroﬁbrillary tangle formation, and cerebral parenchyma deposition of the beta-amyloid protein in the form of amyloid plaques is the domino effects of AD^12-25. The foregoing numbers point to a rapid growth in the global prevalence of AD, even though available therapies are few and consistent^26,27. The amyloid precursor protein (APP) gene is found on chromosome 21q and produces a protein known as APP. Several secretase enzymes like Alpha, Beta and Gama cleave this protein. When the beta-and gama-secretase enzymes cleave the APP, a protein is formed that can accumulate and form plaques in the brain, causing neuronal degeneration. APP and PSEN-1 gene mutations consequence in primary beginning AD; Apolipoprotein E mutation is employed in late-onset AD whereas PSEN-2 has an added inconstant onset. Aging and cognitive decline are resulted due to free radical damage in elderly population. It occurs when there is no balance between protective antioxidant mechanisms and free radical species^28-31. Due to their better biosafety profile than conventional drugs, herbal medications are attracting universal acclaim in more than 80 percent of the world's population.

Main Target Receptors and Protein Related with AD:

N-methyl D-Aspartic Acid receptor is related to AD. GluN1, GluN2A, GluN2B, GluN2C, GluN2D, GluN3A, GluN3B are the prototypes of NMDA receptors present in brain. In both synaptic and extra synaptic positions on neurons, NMDA Receptors are present. Tau protein, cell membrane-associated protein, is in neuronal cells. It brings stabilization of microtubule integrity. Aggregation of these Tau proteins promotes the generation of neurotoxicity, thus the main aim for the therapeutic molecules should be prevention of this accumulation of Tau^32-38.

Pharmacological Profile of Brahmi on Neuro-Degenerative AD:

AD patients contain meaningfully higher levels of acrolein in vulnerable brain region like hippocampus in their brain. Hydrogen peroxide is the substance that contributes toxic effects to the amyloid-β peptide. Brahmi extract has been shown to shield human neuroblastoma cell line SK-N-SH from H₂O₂-and acrolein-induced toxicity. Brahmi provided cyto-protection by scavenging ROS and protecting mitochondrial membrane integrity. Bacosides prevent the beta amyloid protein deposition in brain cortex and support to maintain the normal brain functions. Its anti-stress property helps to maintain the level of reactive oxygen^39-45. The neuronal effects of Bacopa have been proved by several experiments. These are noted as following-

The effect of an alcoholic extract of BM on an animal model of AD caused by ethyl-choline aziridinium ion was investigated, and it was discovered that the extract increased escape latency time in the Morris water maze test. The loss of neurons and cholinergic neuron density was also decreased⁴⁶. A research work found that when 300 mg of standardized extract of Brahmi was taken by oral two times a day for six months, cognitive functions of AD patients improved. An ethanol extract of BM was shown to have anti-acetylcholinesterase properties in a sample. In a male albino rat (225-250 g), an in vivo analysis of the effect of ethanol extract was conducted in which an oral dosage of 100 mg/kg of body weight ethanolic extracts was given for fifteen days and it inhibited acetylcholine-esterase activity competitively in various brain regions⁴⁷.

Mechanism of Brahmi in Protection Against Neuroinflammation-

In lipopolysaccharide (LPS)-induced N9 microglial cells, lower doses of Brahmi extract therapy were found to reduce interleukin and Tumor Necrosis Factor levels. According to reports, Brahmi inhibited caspase-10 in cells, which resulted in a decrease in neuroinflammation. Furthermore, a Brahmi-derived peptide was discovered to upsurge caspase-3 function, while Brahmi leaf extract was discovered to lower caspase-3 levels in a sodium nitroprusside-treated human embryonic lung epithelial cell line (L132). Brahmi produces betulinic acid (BA), which is a bioactive component. It decreases prostaglandin production as well as reduce cyclooxygenase- 2 activity. These properties of Brahmi help it in the treatment of neuroinflammation^48,49,50. Polyphenolic compounds and sulfhydryl components are present in BM extract. Tembhre stated that BM elicited acetylcholinesterase inhibitory action in cerebral cortex of rat and kinetic experiments exhibited that there was a competitive acetylcholinesterase inhibition in the brain regions^51-56. Minimization of tau protein hyper polarization by Brahmi has been explained in Figure 6 and 7.

‘Bacognize’ an important active constituent of Brahmi:

According to Kumar et al experiment, it had been evaluated that a significant improvement in the tests relating to the cognitive functions in the participants occurred who had taken 150mg of Bacognize. One problem of that active component is lower solubility⁵⁷. Thakkar et al overcame this problem by using inclusion complex of Bacognize and β-cyclodextrin⁵⁸.

Diabetic Neuropathy:

DPN is one of the more prominent difficulties of long-term hyperglycemia, with clinically relevant morbidity. Diabetic patients have risen significantly globally, and the numeral figure of diabetic patients is projected to exceed 300 million by 2025 approximately^59-63. Stimulation of the polyol pathway enhanced advanced glycation end products (AGEs) and their receptors, stimulation of protein kinase C (PKC), mitogen-activated protein kinases (MAPK), and inducible nitric oxide synthase are all examples of well-known biochemical pathways activated by hyperglycemia. The procedure of reactive di-carbonyls forming AGEs because of hyperglycemia has been identified as one mechanism that plays a noteworthy role in the pathogenesis of sensory neuron injury. Both channels, when combined, create an imbalance in the cell's mitochondrial redox state, resulting in an accumulation of reactive oxygen species (ROS) production^64,65,66.

The pathogenesis of diabetic neuropathy has been related to ROS, the development of AGEs, and apoptosis. In the pathogenesis of diabetes and diabetic complications, oxidative stress is also an important factor. Excessive free radical development arises in diabetes because of glucose oxidation, non-enzymatic protein glycation, and other causes. Excessive amounts of free radicals can cause lipid peroxidation, enzyme system impairment, and cellular organelle damage. Insulin resistance may also be a consequence of it^60,67,68. Pharmacological reason of DPN has been described in Figure 8.

Figure. 8- Schematic diagram of diabetic neuropathy

Effectiveness of Brahmi in Diabetic Neuropathy:

Kishore L et al performed an experiment on diabetic rats by taking BM alcohol extract and Bacosine for 30 days treatment schedule. They stated that via regulation of oxidative-nitrosative stress and depletion in AGEs development in diabetic rats, BA and BS repaired hyperglycaemia and partly reversed the pain response, suggesting that it could be used to treat neuropathic pain in diabetic patients⁶⁹.

Major Adverse Effects of Bacopa:

As it has high therapeutic index value, it possesses very little adverse effects on human and animal like nausea, excess gastrointestinal motility, reduction of ability in fertilization⁷⁰. Other than these, no hematological and neurological side effects have not been reported.

CONCLUSION:

Tau protein aggregation as well as alternation of NMDA receptor activity result AD. This disease is a form of senile dementia due to amyloid plaque formation in the hippocampus. Neuropathic pain is also a worldwide issue. Despite advancements in medicine and new drug discovery methods, effective medications to relieve the effects of neuropathic pain remain rare. Here the dammarane type triterpenoid saponins present in Brahmi have been discussed for their important pharmacological roles in the treatment of AD as well as DPN. But some limitations have also been noticed.

The action of Brahmi extract on Tauopathies has yet to be investigated. As a result, studies on the function of Brahmi extract in preventing Tau aggregation will guide future research into finding a cure for AD. Brahmi, a nootropic herb, is known to improve cell metabolism by lowering a number of hazard reasons. As a result, the neuroprotective efficacy of Brahmi in various neurodegenerative disorders, as well as potential applications of Brahmi in AD, are the main topics covered in this study.

BM's antinociceptive effect on neuropathic pain demands more research not only to elucidate the exact cause, but also to be studied in other neuropathic pain models due to variations in the severity of each pain component between animal models.

These limitations should be further studied and perform research on this area to clear the complete effectiveness of Brahmi on problem related nervous system.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

REFERENCES:

1. Sharma S. Rathi N. Kamal B. Conservation of biodiversity of highly important medicinal plants of India through tissue culture technology- a review. Agriculture and Biology Journal of North America. 2010; 1(5):827-833. doi/10.5251/abjna.2010.1.5.827.833

2. Murthy PBS. Raju VR. Ramakrishna T. Chakravarthy MS. Kumar KV. Kannababu S et al Estimation of twelve bacopa saponins in Bacopa monnieri extracts and formulations by high-performance liquid chromatography. Chemical and Pharmaceutical Bulletin. 2006; 54(6):907–911. doi/10.1248/cpb.54.907

3. Deepak M. Sangli GK. Amit A. Quantitative determination of the major saponin mixture bacoside a in Bacopa monnieri by HPLC. Phytochemical Analysis. 2005; 16(1):24–29. doi/10.1002/pca.805

4. Deepak M. Amit A. ‘Bacoside B’ - the need remains for establishing identity. Fitoterapia. 2013; 87:7–10. doi: 10.1016/j.fitote.2013.03.011

5. Shinomol GK. Bharath MMS. Exploring the Role of “Brahmi” (Bocopa monnieri and Centella asiatica) in Brain Function and Therapy, Recent Patents on Endocrine. Metabolic & Immune Drug Discovery. 2011; 5:33-49. doi/10.2174/187221411794351833

6. Banerjee A. Schepmann D. Kohler J. Würthwein EU. Wünsch BU. Synthesis and SAR studies of chiral non-racemic dexoxadrol analogues as uncompetitive NMDA receptor antagonists. Bioorganic & Medicinal Chemistry. 2010; 18:7855–7867. doi/ 10.1016/j.bmc.2010.09.047

7. Chen HS. Lipton SA. Mechanism of memantine block of NMDA-activated channels in rat retinal ganglion cells. Journal of Physiology. 1997; 499 (1):27–49. doi/10.1113/jphysiol. 1997.sp021909

8. Chen HS. Pellegrini JW. Aggarwal SK. Lei SZ. Jensen FE. Liptpn SA. Open-channel block of N-methyl-D-aspartate (NMDA) responses by memantine: therapeutic advantage against NMDA receptor-mediated neurotoxicity. Journal of Neurological science. 1992; 12(11):4427–4436. doi/ 10.1523/JNEUROSCI.12-11-04427.1992

9. Winblad B. Poritis N. Memantine in severe dementia: results of the 9M-Best Study (Benefit and efficacy in severely demented patients during treatment with memantine). International Journal of Geriatric Psychiatry. 1999; 14(2):135–146. doi/10.1002/(sici)1099-1166(199902)14:2<135:aid-gps906>3.0.co;2-0

10. Reisberg B. Doody R. Stöffler A. Schmitt F. Ferris S. Mobius HJ. Memantine in moderate-to-severe Alzheimer’s Disease. New England Journal of Medicine. 2003; 348(14):1333–1341. doi/10.1056/NEJMoa013128

11. Tamilselvan M. Tamilanban T. Chitra V. Unfolding Remedial Targets for Alzheimer’s Disease. Research J. Pharm. and Tech 2020; 13(6):3021-3027. doi/10.5958/0974-360X.2020.00534.X

12. Zhang Y. Li P. Feng J. Wu M. Review on Dysfunction of NMDA receptors in Alzheimer’s Disease. Neurological Science. 2016, 37:1039–1047. doi/10.1007/s10072-016-2546-5

13. Maragos WF. Greenamyre JT. Penney JB. Young AB. Glutamate dysfunction in Alzheimer's Disease: a hypothesis. Trends in neurosciences. 1987; 10(2):65-8doi/10.1016/0166-2236(87)90025-7

14. Surabhi. Singh BK. Alzheimer’s Disease: a comprehensive review. International Journal of Pharmaceutical Science and Research. 2019; 10(3):993-1000. doi/ 10.13040/IJPSR.0975-8232.10(3).993-00

15. Bhushan I. Kour M. Kour G. Gupta S. Sharma S. Yadav A. Alzheimer’s Disease: Causes & treatment – A review. Annals of Biotechnology. 2018; 1(1):1002. doi/10.33582/2637-4927/1002

16. Herholz K. Ebmeier K. Clinical amyloid imaging in Alzheimer’s Disease. Lancet Neurology. 2011; 10:667–70. doi/ 10.1016/S1474-4422(11)70123-5

17. Kabir T. Sufian MA. Uddin MS. Begum MM. Akhter S. Islam A et al NMDA Receptor Antagonists: Repositioning of Memantine as a Multitargeting Agent for Alzheimer's Therapy. Current Pharmaceutical Design. 2019; 25(33):3507-14. doi/10.2174/1381612825666191011102444

18. Uddin MS. Mamun AA. Takeda S. Sarwar MS. Begum MM. Analyzing the chance of developing dementia among geriatric people: a cross-sectional pilot study in Bangladesh. Psychogeriatrics. 2019; 19(2):87-94. doi/ 10.1111/psyg.12368

19. Puzzo D. Privitera L. Dale E. Fa M. Picomolar amyloid-beta positively modulates synaptic plasticity and memory in hippocampus. Journal of Neuroscience. 2008; 28(53):14537-45. doi/10.1523/JNEUROSCI.2692-08.2008

20. Lee HG. Perry G. Moreira PI. Garrett MR. Tau phosphorylation in Alzheimer’s Disease: pathogen or protector? Trends in Molecular Medicine. 2005; 11(4):164-9. doi/ 10.1016/j.molmed.2005.02.008

21. Velraj M. Lavaniya N. Alzheimer’s Disease and a Potential Role of Herbs-A Review. Research J. Pharm. and Tech. 2018; 11(6):2695-2700. doi/ 10.5958/0974-360X.2018.00498.5

22. Dhinakaran S. Tamilanban T. Chitra V. Targets for Alzheimer’s Disease. Research J. Pharm. and Tech. 2019; 12(6):3073-3077. doi/ 10.5958/0974-360X.2019.00521.3

23. Srikanth Y. Tamilanban T. Chitra V. Medicinal plants Targeting Alzheimer’s Disease - A Review. Research J. Pharm. and Tech. 2020; 13(7):3454-3458. doi/ 0.5958/0974-360X.2020.00613.7

24. Venkatachalam S. Jaiswal A. De A. Vijayakumar RK. Repurposing Drugs for Management of Alzheimer Disease. Research J. Pharm. and Tech. 2019; 12(6):3078-3088. doi/10.5958/0974-360X.2019.00522.5

25. Sanmugam K. Depression is a Risk Factor for Alzheimer Disease- Review. Research J. Pharm. and Tech. 2015; 8(8):1056-1058. doi/10.1001/archpsyc.63.5.530

26. Markowitsch HJ. Staniloiu A. Amnesic disorders. Lancet. 2012; 380:1429–1440. Doi/ 10.1016/S0140-6736(11)61304-4

27. Scoville WB. Milner B. Loss of recent memory after bilateral hippocampal lesions. Journal of Neurology, Neurosurgery and Psychiatry. 1957; 20:11–21. doi/ 10.1136/jnnp.20.1.11

28. Selkoe DJ. Alzheimer’s Disease: genes, proteins, and therapy. Physiological Reviews. 2001; 81:741– 766. doi/ 10.1152/physrev.2001.81.2.741

29. Priller C. Bauer T. Mitteregger G. Krebs B. Kretzschmar HA. Herms J. Synapse formation and function is modulated by the amyloid precursor protein. Journal of Neuroscience. 2006; 26:7212–7221. doi/10.1523/JNEUROSCI.1450-06.2006

30. Choudhury S. Vellapandian C. Alzheimer’s Disease Pathophysiology and its Implications. Research J. Pharm. and Tech. 2019; 12(4):2045-2048. doi/ 10.5958/0974-360X.2019.00338.X

31. Aanandhi MV. Kumar YP. Chowdary BRP. Praveen D. A Review on the Role of Presenilin in Alzheimer’s Disease. Research J. Pharm. and Tech. 2018; 11(5):2149-2151. doi/ 10.5958/0974-360X.2018.00397.9

32. Balmik AA. Chinnathambi S. Multi-faceted role of melatonin in neuroprotection and amelioration of Tau aggregates in Alzheimer’s Disease. Journal of Alzheimer's Disease. 2018; 62(4):1481-1493. doi/ 10.3233/JAD-170900

33. Citron M. Alzheimer’s Disease: strategies for disease modification. Nature Reviews Drug Discovery 2010; 9:387−398. doi/ 10.1038/nrd2896

34. Nordberg A. Neuroreceptor changes in Alzheimer disease. Cerebrovascular and Brain Metabolism Reviews. 1992; 4:303−328. PMID: 1486017

35. Xia P. Chen HSV. Zhang D. Lipton SA. Memantine preferentially blocks extra synaptic over synaptic NMDA receptor currents in hippocampal autapses. Journal of Neuroscience. 2010; 30:11246−11250. doi/ 10.1523/JNEUROSCI.2488-10.2010

36. Sonkusare SK. Kaul CL. Ramarao P. Dementia of Alzheimer’s Disease and other neurodegenerative disorders—memantine, a new hope, Pharmacological Research. 2005; 51:1–17. doi/ 10.1016/j.phrs.2004.05.005

37. Khachaturian ZS. Diagnosis of Alzheimer’s Disease. Archieves of Neurology. 1985; 42:1097–105. doi/ 10.1001/archneur.1985.04060100083029

38. Karthika S. Kannappan N. Suriyaprakash TNK. Effect of Medicinal plants on amyloid β1-42 Intoxicated SH-SY5Y cell Lines - As Neuroprotective Evaluation. Research J. Pharm. and Tech. 2020; 13(7):3351-3355. doi/ 10.5958/0974-360X.2020.00595.8

39. Vishnupriya P. Padma VV. A Review on the Antioxidant and Therapeutic Potential of Bacopa monnieri. Reactive Oxygen Species. 2017; 3(8):111–120. doi/ 10.20455/ROS.2017.817

40. Singh RH. Narsimhamurthy K. Singh G. Neuro nutrient impact of Ayurvedic Rasayana therapy in brain aging. Biogerontology. 2008; 9:369-74. doi/ 10.1007/s10522-008-9185-z

41. Chakravarty AK. Sarkar T. Masuda K. Shiojima K. Nakane T. Kawahara N. Bacopaside I and II: Two pseudo jujubogenins glycosides from Bacopa monnieri. Phytochemistry. 2001; 58:5536. doi/ 10.1016/s0031-9422(01)00275-8

42. Mahato SB. Garai S. Chakravarty AK. Bacopa saponins E and F: Two jujubogenin bisdesmosides from Bacopa monnieri. Phytochemistry. 2000; 53:711-4. doi/ 10.1016/s0031-9422(99)00384-2

43. Hosamani R. Muralidhara. Neuroprotective efficacy of Bacopa monnieri against rotenone induced oxidative stress and neurotoxicity in Drosophila melanogaster. Neurotoxicology. 2009; 30:977-85. doi/ 10.1016/j.neuro.2009.08.012

44. Chowdhuri DK. Parmar D. Kakkar P. Shukla R. Seth PK. Srimal RC. Antistress effects of bacosides of Bacopa monnieri: Modulation of Hsp70 expression, superoxide dismutase and cytochrome P450 activity in rat brain. Phytotherapy Research. 2002; 16:639-45. doi/ 10.1002/ptr.1023

45. Saraf MK. Prabhakar S. Anand A. Neuroprotective effect of Bacopa monnieri on ischemia induced brain injury. Pharmacology Biochemistry Behaviour. 2010; 97:192-7. doi/ 10.1016/j.pbb.2010.07.017

46. Aswathi T. Venkateswaramurthy N. Sambath Kumar R. A Review on Relevance of Herbal Medications for Psychiatric Patients. Research J. Pharm. and Tech. 2019; 12(7):3151-3156. doi/ 10.5958/0974-360X.2019.00531.6

47. Das A. Shanker G. Nath C. Pal R. Sing S. Sing H. A comparative study in rodents of standardized extracts of Bacopa monniera and Ginkgo biloba: anticholinesterase and cognitive enhancing activities. Pharmacol Biochem Behav. 2002; 73(4):893-900. doi/ 10.1016/s0091-3057(02)00940-1

48. Debnath T. Kim D. Lim B. Natural products as a source of anti-inflammatory agents associated with inflammatory bowel disease. Molecules. 2013;18(6):7253-7270. doi/ 10.3390/molecules18067253

49. Anand T. Pandareesh MD. Bhat PV. Venkataramana M. Anti-apoptotic mechanism of Bacoside rich extract against reactive nitrogen species induced activation of iNOS/Bax/caspase 3 mediated apoptosis in L132 cell line. Cytotechnology. 2014; 66(5):823-838. doi/ 10.1007/s10616-013-9634-7

50. Kalyani MI. Lingaraju, SM. Salimath BP. A pro-apoptotic 15-kDa protein from Bacopa monnieri activates caspase-3 and downregulates Bcl-2 gene expression in mouse mammary carcinoma cells. Journal of natural medicines. 2013; 67(1):123-136. doi/ 10.1007/s11418-012-0661-z

51. Calabrese C. Gregory WL. Leo M. Kremer D. Bone K. Oken B. Effects of a standardized Bacopa monnieri extract on cognitive performance, anxiety, and depression in the elderly: a randomized, double-blind, placebo-controlled trial. Journal of Alternative and Complementary Medicine. 2008; 14:707–713. doi/ 10.1089/acm.2008.0018

52. Stough C. Scholey A. Cropley V. Wesnes K. Zangara A. Pase M et al Examining the cognitive effects of a special extract of Bacopa monniera (CDRI08: Keenmnd): a review of ten years of research at Swinburne University. Journal of Pharmaceutical Science. 2013; 16:254–258. doi/ 10.18433/j35g6m

53. Downey LA. Kean J. Nemeh F. Lau A. Poll A. Gregory R et al An acute, double-blind, placebo-controlled crossover study of 320 mg and 640 mg doses of a special extract of Bacopa monnieri (CDRI 08) on sustained cognitive performance. Phytotherapy Research. 2013; 27:1407–1413. doi/ 10.1002/ptr.4864

54. Rai R. Singh HK. Prasad S. A special extract of Bacopa monnieri (CDRI-08) restores learning and memory by upregulating expression of the NMDA receptor subunit GluN2B in the brain of scopolamine-induced amnesic mice. Evidence Based Complementary and Alternative Medicine. 2015; 2015:254303. doi/ 10.1155/2015/254303

55. Rajan KE. Preethi J. Singh HK. Molecular and functional characterization of Bacopa monniera: a retrospective review. Evidence Based Complementary and Alternative Medicine. 2015; 2015:945217. doi/ 10.1155/2015/945217

56. Saraf MK. Prabhakar S. Khanduja KL. Anand A. Bacopa monniera attenuates scopolamine-induced impairment of spatial memory in mice. Evidence Based Complementary and Alternative Medicine. 2011; 2011:236186. doi/ 10.1093/ecam/neq038

57. Kumar N. Abichandani LG. Thawani V. Gharpure KJ. Naidu MUR. Ramana GV. Efficacy of standardized extract of Bacopa monnieri (Bacognize®) on cognitive functions of medical students: a six-week, randomized placebo-controlled trial. Evidence Based Complementary and Alternative Medicine. 2016; 2016:4103423. doi/ 10.1155/2016/4103423

58. Thakkar VT. Deshmukh A. Hingorani L. Juneja P. Baldaniya L. Patel A et al Development and optimization of dispersible tablet of Bacopa monnieri with improved functionality for memory enhancement. Journal of Pharmacy and Bioallied Science. 2017; 9:208–215. doi/ 10.4103/jpbs.JPBS_8_17

59. Balakumar P. Arora M. Ganti SS. Reddy J. Recent advances in pharmacotherapy for diabetic nephropathy: Current perspectives and future directions. Pharmacological Research. 2009; 60:24–32. doi/ 10.1016/j.phrs.2009.02.002

60. Kaur N. Kishore L. Singh R. Attenuating diabetes: What really works? Current Diabetes Reviews. 2016; 12:259–278. doi/ 10.2174/1573399811666150826115410

61. Baynes JW. Role of oxidative stress in development of complications in diabetes. Diabetes. 1991; 40:405-412. doi/ 10.2337/diab.40.4.405

62. Said G. Diabetic neuropathy—a review. Neurology. 2007; 3(6):331-339. doi/ 10.1038/ncpneuro0504

63. Martin CL. Albers J. Herman WJ. Cleary P. Waberski B. Greene DA et al Neuropathy among the Diabetes Control and Complications Trial Cohort 8 years after trial completion. Diabetes Care. 2006; 29:340–344. doi/ 10.2337/diacare.29.02.06.dc05-1549

64. Oates PJ. Polyol pathway and diabetic peripheral neuropathy. International Review of Neurobiology. 2002; 50:325–392. doi/ 10.1016/s0074-7742(02)50082-9

65. Tomlinson DR. Mitogen-activated protein kinases as glucose transducers for diabetic complications. Diabetologia. 1999; 42:1271–1281. doi/ 10.1007/s001250051439

66. Toth C. Ronh LL. Yang C. Martinez J. Song F. Ramji N et al Receptor for advanced glycation end products (RAGEs) and experimental diabetic neuropathy. Diabetes. 2008; 57:1002–1017. doi/10.2337/db07-0339

67. Dahiya RS. Kaur N. Kishore L. Gupta GK. Management of diabetic complications: A chemical constituents-based approach. Journal of Ethnopharmacology. 2013; 150:51-70. doi/ 10.1016/j.jep.2013.08.051

68. Shahid M. Subhan F. Ahmad N. Ullah I. A bacosides containing Bacopa monnieri extract alleviates allodynia and hyperalgesia in the chronic constriction injury model of neuropathic pain in rats. BMC Complementary and Alternative Medicine. 2017; 17:293. doi/ 10.1186/s12906-017-1807-z

69. Kishore L. Kaur N. Singh R. Bacosine isolated from aerial parts of Bacopa monnieri improves the neuronal dysfunction in Streptozotocin-induced diabetic neuropathy, Journal of Functional Foods. 2017; 34:237–247. doi/ 10.1016/j.jff.2017.04.044

70. Morgan A. Stevens J. Does Bacopa monnieri improve memory performance in older persons? Results of a randomized, placebo-controlled, double-blind trial. Journal of Alternative and Complementary Medicine. 2010; 16:753–759. doi/10.1089/acm.2009.0342

Received on 13.04.2021 Modified on 07.09.2021

Research J. Pharm. and Tech. 2022; 15(8):3790-3795.

DOI: 10.52711/0974-360X.2022.00636