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Home > Pharmacological Efficacy of Systemic and Topical 6-Methoxyflavone and Bacopa Monnieri in the Rodent Neuropathic Nociceptive Paradigms

Pharmacological Efficacy of Systemic and Topical 6-Methoxyflavone and Bacopa Monnieri in the Rodent Neuropathic Nociceptive Paradigms

Thesis Info

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Author

Shahid, Muhammad

Program

PhD

Institute

University of Peshawar

City

Peshawar

Province

KPK

Country

Pakistan

Thesis Completing Year

2019

Thesis Completion Status

Completed

Subject

Pharmacy

Language

English

Link

http://prr.hec.gov.pk/jspui/bitstream/123456789/11845/1/Complete%20thesis29_M%20Shahid_PhD_Pharmacy_Reports7.pdf

Added

2021-02-17 19:49:13

Modified

2024-03-24 20:25:49

ARI ID

1676726877537

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Neuropathic pain occurs due to a lesion or disease process affecting the somatosensory system. This pain is usually presented as an evoked response to non-painful stimuli (allodynia) and an exaggerated response to potentially painful stimuli (hyperalgesia). Despite rapid advancement of neuroscience and modern techniques related to drug design, effective drugs to mitigate the painful symptoms of neuropathy are still lacking. Systemic pharmacotherapy is currently regarded as the mainstay treatment and guidelines suggest offering a choice of gabapentin, pregabalin, amitriptyline, duloxetine, and tramadol. Unfortunately, the clinical effectiveness of these systemic agents can be limited by the extent of pain relief provided and the occurrence of significant side-effects. These limitations may be curtailed by investigating additional safe and effective agents and by localized therapy. In the present study, the flavonoid 6-methoxyflavone and a standardized extract of Bacopa monnieri (L.) Pennell (family: Scrophulariaceae), a widely reputed nootropic plant, were investigated via the systemic and topical routes for prospective neuropathic pain attenuating efficacy in the well-established rat models of chronic constriction injury of the sciatic nerve (CCI), cisplatin and streptozotocin induced neuropathic nociception. The neuropathic paradigms measured were static and dynamic mechanical allodynia (paw withdrawal threshold [PWT] to von Frey monofilaments and latency [PWL] to light brushing with a cotton bud), cold allodynia (paw withdrawal duration [PWD] to an acetone drop), heat hyperalgesia and hypoalgesia (increase and decrease PWL to a heat stimulus) and mechano-hyperalgesia (PWD to pin-prick), static and dynamic mechanical vulvodynia (flinching response threshold to the von Frey filaments pressure [FRT] and latency to light brushing [FRL] of the vulvar region). Additionally, any effect on the neuronal function produced after systemic and topical treatments was assessed using the paradigms of open field, rotarod, and footprint pattern analysis. For the systemic treatment, the antinociceptive doses for 6-methoxyflavone were 25, 50, and 75 mg/kg, while those of B. monnieri were 40 and 80 mg/kg. Gabapentin at 75 mg/kg was used as positive control. Topical gels of 6-methoxyflavone and B. monnieri were prepared in concentrations of 6% and 10% in relation to the clinically effective gabapentin gel. The relevant neuropathic nociceptive paradigms were successfully expressed in the operated hindpaw after placement of four loose ligatures around the sciatic nerve (days 3-21) and in both the hindpaws during the four weekly cisplatin injections and after the single injection of streptozotocin (days 7-28). These were exemplified as a significant decreased PWT to von Frey monofilaments, decreased PWL to cotton bud stroking and heat as well as an increased PWL to heat (cisplatin only), increased PWD to a drop of acetone and pin-prick, and decreased FRT to von Frey filaments and FRL to cotton bud (streptozotocin only). The daily systemic doses of 6-methoxyflavone and B. monnieri significantly attenuated the overall maintenance of mechanical and cold allodynia, mechanical and thermal hyperalgesia, heat hypoalgesia, and tactile vulvodynia during the expression days. Similarly, gabapentin treatment also afforded an analogous beneficial behavioral profile. The three times daily applications of the topical gels of 6-methoxyflavone and B. monnieri ipsilaterally but not contralaterally alleviated the neuropathic aberrations in the CCI induced nociception model and also in the cisplatin and streptozotocin induced polyneuropathy in both hindpaws. Accordingly, daily application of gabapentin gel on the mid-plantar area also showed a comparable suppression of neuropathic expression. However, the antinociceptive actions of gabapentin via the systemic route were associated with immobility along with motor impairment exemplified by a significant decrease in rotarod endurance latency and a deficit in the uniformity of step alternation. In Summary 3 contrast, the systemic and topical 6-methoxyflavone and B. monnieri were devoid of these unwanted effects and in fact the systemic treatments corrected these neuronal dysfunctions specifically associated with cisplatin and streptozotocin neuropathic models. The gabapentin 10% gel also afforded desirable neuropathic pain alleviating effects devoid of unwanted systemic side-effects, thereby indicating local antinociceptive actions for the topical gels. These outcomes suggest that systemic treatment with 6-methoxyflavone and B. monnieri afforded desirable neuropathic pain alleviating propensities when tested against an extensive range of nociceptive stimulus modalities without producing any gabapentin-like unwanted motoric side-effects. These findings also disclosed an expedient pharmacological validation of the effectiveness of topical route in the management of neuropathic pain. The systemic and topical 6-methoxyflavone and Bacopa monnieri can be used as an adjuvant therapy for pain conditions including neuropathic pain afflicted with allodynia and hyperalgesia and/or heat hypoalgesia as well as for diabetes associated vulvar pain. Further studies are advocated in other animal models along with clinical studies with regard to certain neuropathic pain syndromes in addition to elaborate pharmacodynamic and pharmacokinetic evaluation.
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غزل

کشتیوں سے اتر نہ جائیں کہیں

لوگ طوفان سے ڈر نہ جائیں کہیں

 

زندگی ہے کہ آگ کا دریا

شدت غم سے مر نہ جائیں کہیں

 

جن کو ظلمت نے باندھ رکھا ہے

چاندنی میں بکھر نہ جائیں کہیں

 

روک اشکوں کو اب سر مژگاں

یہ بھی حد سے گزر نہ جائیں کہیں

 

آؤ لکھ لیں لہو سے عہد وفا

قول سے ہم مکر نہ جائیں کہیں

 

ان کی یادوں کے زخم اے عالمؔ

وقت سے پہلے بھر نہ جائیں کہیں

معاصر مسلم تعلیمی حالت اور مستقبل کے چیلنجز: پاکستان کے تناظر میں

The history of Muslim Education reveals that there was no difference of materialistic and religious education in the past. However, for the last two centuries, Muslim world divided into many ideologies which consequently produced separate educational institutions for every ideology. In the secular/modern educational institutions, religious and metaphysical studies are missing while, on the other hand, religious seminaries focus on the pure religious education. In such a situation, two kinds of students are graduating from our educational institutions which do not have congruence in practical life with each other. Present Muslim world in dire need of a comprehensive educational system combining the modern secular and religious subjects in an appropriate manner. Currently, if Islamic world is distressed technologically at one hand, it is divided in many sects, on the other. Therefore, acquisition of scientific and religious, both kinds of education are required for Muslims. In the present paper, the responsibilities of Muslim world are discussed to face the current and future challenges from educational perspective in order to portray a true picture of Islam and its followers.

Effects of Amendments and Irrigation Water Composition on Salt Leaching from Different Textured Soils and Amelioration of Saline- Sodic Soils for Crop Production

Soil degradation caused by salinization and/or sodification is of great concern in modern world because it reduces potential of agricultural lands. It usually leads to deteriorate soil properties like structure, water retention, porosity, electrical conductivity, sodium adsorption ratio and soil flora and fauna. Mostly saline-sodic and/or sodic soils have poor internal drainage which otherwise is pre-requisite for their reclamation. The present studies were conducted to evaluate differential response of soil texture for leaching of salts under different treatments. Three experiments were conducted in the wire house to evaluate the leaching response of different textured (loamy sand, silty clay loam and sandy clay loam) soils. In Study1, different pore volumes of water were added to evaluate the leaching response of different textured soils. The highest amount of salts was removed from SCL soil (1943 kg ha-1) with leaching fraction (LF) 0.59 with the application of four PV water. The decreasing order of treatment effectiveness for salt removal was T3 > T2 > T4 > T1 with LF 0.69, 0.64, 0.61 and 0.60, respectively. The ECe of 0-25 cm columns (post-experiment) decreased from 8.2 to < 4 dS m-1 in LS with 2.0 PV (1.88 cm), from 33.9 to < 4 dS m-1 in SCL with 2.5 PV (2.67 cm) of applied water and SiCL with 2.5 PV (2.72 cm) of water, it decreased from 23.9 to < 4 dS m-1 only of 0- 10 cm of soil layer. Regarding SAR, 2.5 PV of applied water decreased SAR to < 13 in LS up to 0-20 cm depth, 0-10 cm soil depth of SiCL and 0-15 cm soil depth of SCL. It was found that leaching of soluble slats does occur with simple addition of water of any quality in different textured saline-sodic soils but could convert these into sodic soils if external source of Ca2+ is not added. In study 2, irrigation water of different EC : SAR ratios was used after amending different textured soils with gypsum @ 100% soil gypsum requirement (SGR), farm manure (FM) @ 10 Mg ha-1 and mulch @ 10 Mg ha-1. It was observed that amendments significantly decreased pHs, ECe and SAR of all the three soils using different EC: SAR ratio waters. With four PV of applied water, LF of 0.75, 0.77 and 0.78 was attained that removed 3008, 4965 and 5048 kg ha-1 salts in LS, SiCL and SCL soils, respectively. For the 1st, 2nd, 3rd and 4th irrigations with LF of 0.82, 0.79, 0.75 and 0.71 removed 5682, 5000, 3967 and 2941 kg ha-1 salts, respectively. For amendments, the decreasing order for salt removal was FM > G > M > C with LF= 0.85, 1 0.84, 0.71 and 0.68. The use of amendments in all the three soils decreased the pHs, ECe and SAR of soils that depended upon with different EC to SAR ratio of irrigation waters. Overall, decreasing order of effectiveness of amendments for soil amelioration was FM > G > M > C. In Study 3, pot experiment was conducted following sorghum-oat and rice-wheat crop rotations with same amendments as for Study 2. Three different waters (EC 0.6 + SAR 6, EC 1.0 + SAR 12 and EC 2.0 + SAR 18) were used for irrigation. The results showed that as the brackishness of water increases more salts leached. Water of different EC : SAR ratios (EC 0.6 + SAR 6, EC 1.0 + SAR12 and EC 2.0 + SAR 18) were applied. From results, it may be inferred that 1 PV of brackish water with higher EC: SAR (EC 2 and SAR 18) ratio could be used beneficially, if proper amendments are selected. For rice crop, the order of effective amendments was in the decreasing order of G > FM > M > C. With sorghum, the order was FM > G > M > C. For wheat, the order was FM > G > M > C, and for oat it was G > FM > M > C. Leaching effectiveness decreased with increasing irrigation water salinity without accumulation of salts in soils. It depicts that for initial reclamation of salt-affected soils, low quality irrigation waters could be useful and sometimes even better with amendments than canal water alone owing to favorable effect of electrolytes in former water on soil infiltration and hydraulic conductance. In the present studies, salt removal from soils was the lowest when LF was 0.20 and was the highest when LF was 0.32, i.e. direct positive relationship. The Study 4 was conducted under field conditions following rice-wheat crop rotation using saline-sodic water (SSW), canal water (CW) and their combination. The amendments applied in sub-plots were control, gypsum at 100% SGR, FM at10 t ha-1 and mulch at10 t ha-1. The soil reclamation with respect to pHs, ECe and SAR remained considerably better with the application of gypsum and FM. Overall, the results indicate that amendments like gypsum, FM and mulching could favor the desodication of saline- sodic soils. The soil reclamation with respect to pHs, ECe and SAR remained considerably better with the application of gypsum and FM with all the irrigation waters. It is concluded that cyclic use of SSW and CW could be better for initial reclamation of SiCL soil by following rice-wheat crop rotation. The salt leaching efficiency decreased over time, being highest after rice crop that decreased with time. Gypsum and FM 2 application significantly increased crop yields even with SSW irrigation. Net benefit from rice-wheat rotation was the highest with FM receiving SSW−CW followed by gypsum. Hence gypsum and FM amendments are essential for growing crops during soil reclamation, even if poor quality water is used for irrigation. Since salinity/sodicity has to persist in irrigated agriculture, under arid land conditions, a strong follow up program in such mega development projects must be ensured to harvest maximum and sustainable benefits from such activity.