EVALUATION OF PROTECTIVE EFFECT OF TEST SAMPLE IN PACLITAXEL INDUCED NEUROPATHY PAIN MODEL IN EXPERIMENTAL RAT

 

EVALUATION OF PROTECTIVE EFFECT OF TEST SAMPLE IN PACLITAXEL INDUCED NEUROPATHY PAIN MODEL IN EXPERIMENTAL RAT

1.0  INTRODUCTION:

Chemotherapeutic agents can cause toxic effects on peripheral nerves. Severity may range from loss of sensory function and mild paresthesias to neuropathic pain, severe ataxia and weakness leading to pronounced disability. In tissue culture, Paclitaxel promotes the formation of abnormal bundles of microtubules within the cytoplasm, leading to the disruption of normal cell function and proliferation. Microtubules are important for the development and maintenance of neurons. Microtubule elongation contributes toward the growth of neurites through interactions with the growth cone and they are the major participating elements mediating axonal transport in the neuron.

 

2.0  TEST SYSTEM DETAILS:

Species             : Rattus norvegicus (Rat)

Strain                 : Wistar or Sprague Dawley

Age                    : 8-10 weeks

Body Wight        : 160-180 g

Sex                    : Male or Female

No. of animals   : 8 /Group

 

3.0  ALLOCATION OF GROUPS:

Groups	Treatment	Dose; ROA	No. of Animals
G1	Normal Control	Normal saline or 0.25% Na-CMC	8
G2	Disease Control	Normal saline or 0.25% Na-CMC	8
G3	Reference Drug- Gabapentin	75 mpk; i.p.	8
G4	Plant Extract-1	X mpk; p.o.	8
G5	Plant Extract-2	XX mpk; p.o.	8
G6	Plant Extract-3	XXX mpk; p.o.	8

*The dose and ROA (Routes of administration) will be decided based on the type of reference drug

 

4.0 METHODOLOGY:

·       The study protocol (Form B) shall be approved from the IAEC before commencing the experiment.

·       Animals shall be procured from the CPCSEA authorized vendor.

·       Animals shall be quarantined for 1 week as per the in house SOP.

·       Healthy animals will be selected, randomized based on body weight and divided into five different groups consisting of 8 animals each.

·       Paclitaxel Injection

·       Paclitaxel (6 mg/mL clinical formulation) will be diluted with 0.9% sterile saline to achieve a 2 mg/mL solution.

·       To replicate the clinical formulation of paclitaxel, a vehicle stock solution will be made using 1:1 solution of Cremophor EL and ethanol and will also be contained 2 mg/mL sodium citrate.

·       One part vehicle stock solution will be diluted with 2 parts 0.9% sterile saline in case of vehicle administration.

·       Rats will be received intraperitoneal 2 mg/kg paclitaxel or the equivalent volume of vehicle solution on 4 alternate days 0, 2, 4, and 6.

·       Animals will be administered according to their body weight (1 ml/kg) and immediately returned to their home cages afterwards.

·       All paclitaxel/vehicle injections will be administered in the early afternoon 1–3 pm

·       Both paclitaxel and vehicle solutions will be clear solutions with the same viscosity, which enables blinding procedures.

 

·       Treatment and assessment of neuropathy pain:

·       Group G1 animal will be treated as normal control and treated with normal saline or Na- CMC.

·       Animals of group G2 will be treated as disease control and administered with normal saline or Na- CMC.

·       Group G4, G5 and G6 will be treated with test compound at different dose levels.

·       All the animals will be administered with vehicle or test sample or reference drug on day 0 and continued throughout the experiment.

·       The behavioral tests mechanical allodynia, motor coordination, cold hypersensitivity, and thermal hyperalgesia will be conducted at before paclitaxel injection (Day, 0) and weekly basis after injection (Day, 7, 14, 21, 28).

5.0 END POINT PARAMETER(S):

·       Body Weight

·       Feed water consumption

·       Mechanical allodynia

·       Thermal Hyperalgesia

·       Cold hypersensitivity

·       Serum cytokines - TNF-α and IL-1β

6.0  REFERENCE(S):

6.1 Natalie A. Duggett, Lisa A. Griffiths, Sarah J.L. Flatters. Paclitaxel-induced painful neuropathy is associated with changes in mitochondrial bioenergetics, glycolysis, and an energy deficit in dorsal root ganglia neurons.  Pain. August 2017·Volume 158·Number 8

6.2 Lisa A. Griffiths, Natalie A. Duggett, Ann L. Pitcher, and Sarah J. L. Flatters. Evoked and Ongoing Pain-Like Behaviours in a Rat Model of Paclitaxel-Induced Peripheral Neuropathy. Pain Research and Management Volume 2018, Article ID 8217613, 11 pages https://doi.org/10.1155/2018/8217613.

6.3 Ahmet Höke and Mitali Ray. Rodent Models of Chemotherapy-Induced Peripheral Neuropathy. ILAR Journal, Volume 54, Number 3, doi: 10.1093/ilar/ilt053.

6.4 Charity D. Scriptur, William D. Figg and Alex Sparreboom. Peripheral Neuropathy Induced by Paclitaxel: Recent Insights and Future Perspectives. Current Neuropharmacology, 2006, 4, 165-172.

6.5 Lekha Saha, Debasish Hota, and Amitava Chakrabarti. Evaluation of Lercanidipine in Paclitaxel-Induced Neuropathic Pain Model in Rat: A Preliminary Study. Pain Research and Treatment Volume 2012, Article ID 143579, 5 pages doi:10.1155/2012/143579.

                                   END OF DOCUMENT

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4.List of OECD Guidelines or Toxicological Studies

5.List of Pharmacopeial Test or Quality Control Test or Batch Testing Parameters (In-vivo)

6.EVALUATION OF PROTECTIVE EFFECT OF TEST SAMPLE IN SURGICALLY INDUCED NEUROPATHY PAIN USING CHRONIC CONSTRUCTIVE INJURY (CCI) MODEL IN EXPERIMENTAL RAT

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